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1
Fillit, Howard. "Future Therapeutic Developments of Estrogen Use." Journal of Clinical Pharmacology 35, no. 9S (September 1995): 25S—28S. http://dx.doi.org/10.1002/j.1552-4604.1995.tb04144.x.
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Martin-Jiménez, Cynthia, Diana Milena Gaitán-Vaca, Natalia Areiza, Valentina Echeverria, Ghulam Md Ashraf, Janneth González, Amirhossein Sahebkar, Luis Miguel Garcia-Segura, and George E. Barreto. "Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury." Neuroendocrinology 108, no. 2 (November 4, 2018): 142–60. http://dx.doi.org/10.1159/000495078.
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Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.
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Santen, Richard J., Risa Kagan, Corrado J. Altomare, Barry Komm, Sebastian Mirkin, and Hugh S. Taylor. "Current and Evolving Approaches to Individualizing Estrogen Receptor-Based Therapy for Menopausal Women." Journal of Clinical Endocrinology & Metabolism 99, no. 3 (March 1, 2014): 733–47. http://dx.doi.org/10.1210/jc.2013-3680.
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Context: Adding progestogens to estrogens changes the risk profile of hormonal therapy for menopausal women, and recent data support the need for progestogen-free options. Several current and evolving approaches to managing estrogen deficiency allow for progestogen omission. We review the mechanisms of estrogen activity and provide an overview of emerging and available estrogen receptor (ER)–based therapies. Evidence Acquisition: PubMed was searched for relevant English-language articles using keywords pertaining to estrogen deficiency, menopause, hormone therapy, and estrogen-only therapy. Pivotal or recent randomized controlled trials, large observational studies, comprehensive meta-analyses, and established therapeutic guidelines were compiled. Evidence Synthesis: Advances in our understanding of ER pharmacology have led to therapies designed to optimize ER activity, including selective ER modulators (SERMs) and tissue-selective estrogen complexes (TSECs). Each estrogen, SERM, and TSEC exhibits a unique profile of tissue-specific activity, spanning the spectrum from ER agonism to antagonism. Systemic estrogens unopposed by progestogens effectively manage menopausal symptoms in hysterectomized postmenopausal women but require progestogen use in postmenopausal women with a uterus. SERMs are effective for managing certain aspects of estrogen deficiency in postmenopausal women, but data suggest that pairing a SERM with estrogens to form a TSEC provides a more optimal therapeutic profile for women with a uterus. Conclusions: Treating signs and symptoms of estrogen deficiency requires an individualized approach based on a woman's goals and the purported risks of different therapies. New and emerging agents have demonstrated efficacy in postmenopausal women with a uterus, while allowing these women to avoid progestogens and their possible adverse effects.
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Macciò, Antonio, and Clelia Madeddu. "Obesity, Inflammation, and Postmenopausal Breast Cancer: Therapeutic Implications." Scientific World JOURNAL 11 (2011): 2020–36. http://dx.doi.org/10.1100/2011/806787.
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Breast cancer is the female malignant neoplasia with the highest incidence in the industrialized world. Although early diagnosis has contributed to therapeutic success, breast cancer remains a major health issue. In the last few year the hormone therapy for estrogen-dependent breast cancer has evolved achieving significant clinical results; at the same time, it has enabled us to better define the role of estrogens in the etiopathogenesis of this tumour. Weight increase and obesity have been identified as the most important risk and prognostic factors for breast cancer in postmenopausal women. Several hypotheses have been proposed to explain the association of obesity with postmenopausal breast cancer. Specific obesity-associated factors, including leptin, insulin and inflammatory mediators, seem to influence breast cancer growth and prognosis independently of estrogens and at least in part by interacting with estrogen signalling at a cellular level. Therefore, a careful assessment of the nutritional status and body composition is paramount for a proper therapeutic approach for postmenopausal breast carcinoma. The use of antidiabetic and anti-inflammatory drugs associated with conventional hormone therapies and dietary/physical interventions could offer a new therapeutic approach for breast carcinoma that develops in the context of adiposity.
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Mitra, Saikat, Mashia Subha Lami, Avoy Ghosh, Rajib Das, Trina Ekawati Tallei, Fatimawali, Fahadul Islam, et al. "Hormonal Therapy for Gynecological Cancers: How Far Has Science Progressed toward Clinical Applications?" Cancers 14, no. 3 (February 1, 2022): 759. http://dx.doi.org/10.3390/cancers14030759.
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In recent years, hormone therapy has been shown to be a remarkable treatment option for cancer. Hormone treatment for gynecological cancers involves the use of medications that reduce the level of hormones or inhibit their biological activity, thereby stopping or slowing cancer growth. Hormone treatment works by preventing hormones from causing cancer cells to multiply. Aromatase inhibitors, anti-estrogens, progestin, estrogen receptor (ER) antagonists, GnRH agonists, and progestogen are effectively used as therapeutics for vulvar cancer, cervical cancer, vaginal cancer, uterine cancer, and ovarian cancer. Hormone replacement therapy has a high success rate. In particular, progestogen and estrogen replacement are associated with a decreased incidence of gynecological cancers in women infected with human papillomavirus (HPV). The activation of estrogen via the transcriptional functionality of ERα may either be promoted or decreased by gene products of HPV. Hormonal treatment is frequently administered to patients with hormone-sensitive recurring or metastatic gynecologic malignancies, although response rates and therapeutic outcomes are inconsistent. Therefore, this review outlines the use of hormonal therapy for gynecological cancers and identifies the current knowledge gaps.
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Gérard, Céline, Mélanie Mestdagt, Ekaterine Tskitishvili, Laudine Communal, Anne Gompel, Elisabete Silva, Jean-François Arnal, et al. "Combined Estrogenic and Antiestrogenic Properties of Estetrol on Breast Cancer may provide a Safe Therapeutic Window for the Treatment of Menopausal Symptoms." Journal of SAFOMS 3, no. 1 (2015): 31–33. http://dx.doi.org/10.5005/jsafoms-3-1-31.
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Abstract Increased risk of breast cancer is a critical side-effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. Estetrol (E4) presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERá) is the predominant receptor mediating its effects, the dual weak-estrogenic/antiestrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extranuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms.
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Hwang, Wu Jeong, Tae Young Lee, Nahrie Suk Kim, and Jun Soo Kwon. "The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders." International Journal of Molecular Sciences 22, no. 1 (December 31, 2020): 373. http://dx.doi.org/10.3390/ijms22010373.
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Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.
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Zhao, Zhuo, Hao Wang, Jewell A. Jessup, Sarah H. Lindsey, Mark C. Chappell, and Leanne Groban. "Role of estrogen in diastolic dysfunction." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 5 (March 1, 2014): H628—H640. http://dx.doi.org/10.1152/ajpheart.00859.2013.
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The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.
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Farkas, Szidónia, Adrienn Szabó, Anita Emőke Hegyi, Bibiána Török, Csilla Lea Fazekas, Dávid Ernszt, Tamás Kovács, and Dóra Zelena. "Estradiol and Estrogen-like Alternative Therapies in Use: The Importance of the Selective and Non-Classical Actions." Biomedicines 10, no. 4 (April 6, 2022): 861. http://dx.doi.org/10.3390/biomedicines10040861.
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Estrogen is one of the most important female sex hormones, and is indispensable for reproduction. However, its role is much wider. Among others, due to its neuroprotective effects, estrogen protects the brain against dementia and complications of traumatic injury. Previously, it was used mainly as a therapeutic option for influencing the menstrual cycle and treating menopausal symptoms. Unfortunately, hormone replacement therapy might be associated with detrimental side effects, such as increased risk of stroke and breast cancer, raising concerns about its safety. Thus, tissue-selective and non-classical estrogen analogues have become the focus of interest. Here, we review the current knowledge about estrogen effects in a broader sense, and the possibility of using selective estrogen-receptor modulators (SERMs), selective estrogen-receptor downregulators (SERDs), phytoestrogens, and activators of non-genomic estrogen-like signaling (ANGELS) molecules as treatment.
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Sulaymanova, R. T. "EXPERIMENTAL MODELS OF TRANSGENERATIONAL EFFECTS OF THE INFLUENCE OF ESTROGENS ON THE MORPHOLOGY OF REPRODUCTIVE ORGANS IN POSTNATAL ONTOGENESIS." Morphological newsletter 27, no. 1 (March 30, 2019): 36–44. http://dx.doi.org/10.20340/mv-mn.19(27).01.36-44.
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In the modern clinical practice there is an increase in the use of hormones, their analogues and substances with hormone-like action in medical practice for the regulation of the menstrual cycle, conception, prevention, maintenance and resolution of pregnancy. According to official reports, in recent years, the number of annual cycles of assisted reproductive technology with hormonal support has increased six times in the country. The purpose of the review is to summarize current data on the effects of experimental and clinical effects of various doses of estrogens and drugs with estrogenic effects during the period of prenatal development on the morphology of the reproductive organs of the offspring in postnatal ontogenesis. The materials for the meta-analysis of the data were the results of relevant studies of domestic and foreign authors and their own published data. The article summarizes current data demonstrating the effects of experimental effects of various doses of estrogen and drugs with an estrogenic effect during the period of prenatal development on the morphology of the reproductive organs of the offspring in postnatal ontogenesis. The data on therapeutic, subtoxic and toxic doses of the effects of estrogen preparations in various experimental models are summarized, causing latent and morphologically manifested changes in the reproductive organs of the offspring.
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Normanno, Nicola, Massimo Di Maio, Ermelinda De Maio, Antonella De Luca, Andrea de Matteis, Antonio Giordano, Francesco Perrone, and _. _. "Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer." Endocrine-Related Cancer 12, no. 4 (December 2005): 721–47. http://dx.doi.org/10.1677/erc.1.00857.
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Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogen-independent phenotype. In particular, evidence suggests for each ‘action’ introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding ‘reactions’ that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor α (ERα) and/or increased non-genomic activity of ERα, estrogen supersensitivity, increased growth factor signaling, suppression of ERα expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.
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Elloso, M. Merle, Kristen Phiel, Ruth A. Henderson, Heather A. Harris, and Steven J. Adelman. "Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands." Journal of Endocrinology 185, no. 2 (May 2005): 243–52. http://dx.doi.org/10.1677/joe.1.06063.
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Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERα and ERβ. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17β-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERα-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERβ-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139–151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERβ agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERα-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.
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Manyonda, Isaac, Vikram S Talaulikar, Roxanna Pirhadi, and Joseph Onwude. "Progestogens are the problem in hormone replacement therapy: Time to reappraise their use." Post Reproductive Health 26, no. 1 (December 25, 2019): 26–31. http://dx.doi.org/10.1177/2053369119876490.
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Combined (estrogen and a progestogen) hormone replacement therapy (cHRT) is associated with an increased risk of breast cancer, while estrogen replacement therapy is not. Whatever the underlying mechanism, it is the progestogen in cHRT that seems to increase the risk. Fear of breast cancer is a major limiting factor in the use of hormone replacement therapy, and when women discontinue cHRT because of side effects, the latter are often attributable to the progestogen component. cHRT is given to women with an intact uterus to protect against the effects of un-opposed estrogen such as an increased risk of endometrial cancer. Estrogen replacement therapy suffices for women with a prior hysterectomy. There is a clear distinction in risk and side effect profile between cHRT and estrogen replacement therapy. Apart from being the most effective treatment for menopausal symptoms, estrogen prevents osteoporosis, and may also have a potential role in prevention of Alzheimer’s Dementia, now the biggest killer of women in the United Kingdom. Evidence also suggests that progestogens could compromise the dementia-preventative effect of estrogen. Given the immense therapeutic and preventative potential of estrogen, the use of progestogens in cHRT needs re-appraisal. The levonorgestrel intrauterine system (LNg-IUS) could reduce breast cancer risk while protecting the endometrium. Other approaches to the safe use of progestogens await research.
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Carroll, Kelli J., Michael C. Dovey, Claire C. Cutting, James M. Harris, Lea M. Vedder, Wolfram Goessling, and Trista E. North. "Estrogen Receptors 1 and 2 Have Stage-Specific Effects on Hematopoietic Stem Cell Regulation In Zebrafish." Blood 116, no. 21 (November 19, 2010): 1617. http://dx.doi.org/10.1182/blood.v116.21.1617.1617.
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Abstract Abstract 1617 The intrinsic signaling pathways regulating hematopoietic stem cells (HSC) are increasingly well recognized. However, less is known about how in utero exposure to common environmental xenobiotic compounds may alter HSC development and increase the risk of carcinogenesis. RUNX1 (AML1), required for definitive HSC induction in all vertebrates, is the target of frequent chromosomal alterations associated with leukemia. Through a chemical genetic screen for modifiers of runx1 expression in the zebrafish, estrogen-related compounds were identified. Here, we found that exposure to 17β-estradiol (E2) throughout the initial waves of hematopoietic development (5 somites (som) to 36 hours post fertilization (hpf)) significantly altered the number of runx1+ HSCs in the zebrafish Aorta-Gonad-Mesonephros Region (AGM) compared to controls (n≥25-50 embryos /condition). Other physiological estrogens, such as estrone and estriol, elicited a similar hematopoietic response. However, treatment with either the isomer 17α-estradiol, or the related steroid hormones testosterone or progesterone, could not mimic the effect of E2 on HSCs. Use of the aromatase inhibitor anastrozole and the pan-estrogen receptor inhibitor fulvestrant confirmed that estrogen was both required for nascent HSC regulation and functioned through classical estrogen receptor (esr) signaling. Microarray analysis of FACS-sorted cell populations during zebrafish development demonstrated differential spatio-temporal regulation of esr1 (esrα) and esr2a/b (esrβ) in vascular and hematopoietic cell types. During the primitive wave of hematopoiesis, exposure to E2 and the esr1-agonist PPT significantly enhanced red blood cell number as seen by in situ hybridization for embryonic globin (hbbe3) and quantified by fluorescent microscopy and FACS analysis of the Tg(globin:GFP) line. Conversely, the esr2-specific agonist DPN diminished definitive HSC formation after exposure from 5 som to 24 hpf; this phenotype was mediated by disruption of vessel formation, as indicated by flk1 (kdrl) expression, and alteration in the assignment of artery-vein identity. Interestingly, when exposure to E2 or DPN occurred from 24 – 36 hpf, after the establishment of ephb2+ arteries and the initiation of blood flow, estrogen treatment enhanced HSC formation; this was confirmed by FACS analysis and fluorescent microscopy using the Tg(cmyb:eGFP) and Tg(-6.0itga2b:eGFP)la2 (CD41:GFP) HSC-reporter lines. E2 treatment was found to elicit both pro-apoptotic (TUNEL+) and pro-proliferative (BrdU+) effects on HSCs and the vascular niche depending on the timing of exposure, but independent of the concentration of E2 over the physiological range and above (10nM to 10mM). Morpholino-mediated gene knockdown of esr1 and the two esr2 alleles alone and in combination with E2 confirmed that esr2 was responsible for the effects on definitive hematopoiesis. Using the Tg(TOP:GFP)w25 line, alterations in estrogen signaling were shown to mediate effects on wnt activity. To determine whether exposure to environmental estrogens could mediate similar alterations in HSC specification and proliferation, we exposed embryos to the phytoestrogen genistein, the synthetic estrogen ethinylestradiol, and the xenoestrogen bisphenol A (BPA) and found results reminiscent of E2; using fulvestrant, we confirmed that the phenotype elicited by each was dependent on estrogen receptor stimulation. In an adult zebrafish marrow injury model, E2 significantly enhanced stem and progenitor cell regeneration in males and females by day 10 post irradiation (n≥10 /condition). Intriguingly, we found that females, with higher circulating estrogen levels, recovered better after injury than male siblings, both in the presence and absence of exogenous estrogen. Finally, murine bone marrow treated with E2 or DPN produced significantly (n=10 /condition, p<0.0001) higher numbers of spleen colonies at day 12 post-transplantation than vehicle-only controls, demonstrating functional conservation of estrogenic regulation of HSCs/progenitor cells. These data identify stage-specific, differential roles for estrogen during hematopoiesis, highlighting the potent impact of environmental exposure to estrogenic compounds on blood formation and revealing potential therapeutic options for the treatment of bone marrow failure and leukemia. (equal contribution: KJC, MCD; WG, TEN). Disclosures: Goessling: Fate Therapeutics: Consultancy, Patents & Royalties. North:Fate Therapeutics: Consultancy, Patents & Royalties.
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Petrie, Whitney K., Megan K. Dennis, Chelin Hu, Donghai Dai, Jeffrey B. Arterburn, Harriet O. Smith, Helen J. Hathaway, and Eric R. Prossnitz. "G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth." Obstetrics and Gynecology International 2013 (2013): 1–17. http://dx.doi.org/10.1155/2013/472720.
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Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERαand ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activityin vivoprevents estrogen-mediated tumor growth.
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Yakushevskaya, O. V. "Continuous combined low-dose hormone replacement therapy in perimenopause: an algorithm of choice." Meditsinskiy sovet = Medical Council, no. 3 (April 15, 2021): 113–18. http://dx.doi.org/10.21518/2079-701x-2021-3-113-118.
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In the age of broad medical options, women’s health has received sufficient attention. The different periods of a woman’s life are characterised by specific physiological changes, based on the age-related characteristics of the reproductive system. The onset of menopause can have a negative impact on health in varying degrees. Clinicians have a clear understanding of the effects of estrogen deficiency and the therapeutic options for managing it with menopausal hormone therapy (MHT) and alternative methods of treatment. However, to date, methods for optimising and individualising the correction of menopausal disorders continue to improve. The individualization of MHT is aimed at increasing the efficacy of menopausal management and minimizing possible adverse events. Individualization is based on the selection of a hormone drug taking into account age, menopausal status, somatic health of the woman and her main complaints against the background of estrogen deficiency. The next stage of transformation of MHT concerned the composition of the drugs and the doses of their components. The evolution of the estrogenic component began with the use of conjugated estrogens, whose metabolism is not fully clarified, and stopped at the production of bioidentical estrogens (17p-estradiol and estradiol valerate), which in their structure are as close as possible to ovarian estradiol. The type, dose and combination of estrogens and progestogens determine the severity and specificity of the effect of the hormone. This article will present a clinical case study of the low- and ultra-low-dose combination of 17p-estradiol and dydrogesterone (E/DG).
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Carroll, Kelli J., Michael C. Dovey, Claire C. Cutting, Lea Vedder Sheward, James M. Harris, Wolfram Goessling, and Trista E. North. "Hematopoietic Stem Cell Formation in Zebrafish Is Regulated in a Temporally Distinct Manner by Estrogen Receptor 2." Blood 118, no. 21 (November 18, 2011): 1268. http://dx.doi.org/10.1182/blood.v118.21.1268.1268.
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Abstract Abstract 1268 The intrinsic signaling pathways regulating hematopoietic stem cells (HSC) are increasingly understood; in contrast, less is known about the potential effect of exposure to environmental factors, such as xenoestrogens, on the formation of HSCs. RUNX1 (AML1) is a highly conserved transcription factor that is required for definitive HSC induction and is also the target of many chromosomal alterations in leukemia. Through a chemical genetic screen, estrogen-related compounds were identified as modifiers of runx1 expression in the zebrafish. Exposure to 17b-estradiol (E2) throughout hematopoietic development (5 somites (som) to 36 hours post fertilization (hpf)) significantly decreased the number of runx1+ HSCs in the zebrafish Aorta-Gonad-Mesonephros Region (AGM) compared to controls (n≥25–50 embryos /condition). Use of the nonspecific estrogen receptor inhibitor fulvestrant confirmed that estrogen was required for HSC regulation and functioned through classical estrogen receptors. Microarray analysis of FACS-sorted cell populations during zebrafish development demonstrated differential spatio-temporal regulation and expression of esr1 (esrα) and esr2a/b (esrβ) in vascular and hematopoietic cell types; use of an ERE-GFP reporter fish verified that estrogen signaling is active during this stage of embryonic development. During the primitive wave of hematopoiesis, exposure to E2 and the esr1-agonist PPT significantly enhanced red blood cell number as seen by in situ hybridization for embryonic globin (hbbe3) and quantified by fluorescent microscopy and FACS analysis of the Tg(globin:GFP) line. Conversely, the esr2-specific agonist DPN diminished definitive HSC formation after exposure from 5 som to 24 hpf; this phenotype was mediated by disruption of vessel formation, as indicated by flk1 (kdrl) expression, and alteration in the assignment of artery-vein identity. Alterations in arterial specification appear to be mediated by the Notch/VEGF pathway. E2 exposure from 5 somites to 36 hpf decreased GFP expression in notch reporter fish as well as expression of deltaC and notch5 by in situ hybridization. Interestingly, when exposure to E2 or DPN occurred from 24 – 36 hpf, after arterial establishment and initiation of blood flow, estrogen treatment enhanced HSC formation; this was confirmed by FACS analysis and fluorescent microscopy using the Tg(cmyb:eGFP) and Tg(-6.0itga2b:eGFP)la2 (CD41:GFP) HSC reporter lines. E2 treatment was found to elicit both pro-apoptotic (TUNEL+ and acridine orange) and pro-proliferative (BrdU+) effects on HSCs and the vascular niche depending on the timing of exposure. Morpholino-mediated gene knockdown of esr1 and the two esr2 alleles alone and in combination with E2 confirmed that esr2 was responsible for the effects on definitive hematopoiesis. Using the Tg(TOP:GFP)w25 line, modifications in Wnt activity were seen post-E2 exposure from 24 – 36 hpf. To determine whether environmental estrogens could mediate similar alterations in HSC specification and proliferation, we exposed embryos to the phytoestrogen genistein, the synthetic estrogen ethinylestradiol, and the xenoestrogen bisphenol A (BPA) and found that all decreased formation of HSCs; using fulvestrant and the ERE-GFP reporter, we confirmed that the phenotype elicited by each was at least partially dependent on estrogen receptor stimulation. In an adult zebrafish marrow injury model, E2 significantly enhanced stem and progenitor cell regeneration in males and females by day 10 post irradiation (n≥10 /condition). Intriguingly, we found that females, with higher circulating estrogen levels, recovered better after injury than male siblings, both in the presence and absence of exogenous estrogen. Finally, murine bone marrow treated with E2 or DPN produced significantly (n=10/condition, p<0.0001) higher numbers of spleen colonies at day 12 post-transplantation than vehicle-only controls, demonstrating functional conservation of estrogenic regulation of HSCs/progenitor cells. These data identify stage-specific, differential roles for estrogen during hematopoiesis, highlighting the potent impact of environmental exposure to estrogenic compounds on blood formation and revealing potential therapeutic options for the treatment of bone marrow failure and leukemia. Disclosures: Goessling: Fate Therapeutics: Consultancy. North:Fate Therapeutics: Consultancy.
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Kareva, Kareva E. N., and Smetnik A. A. Smetnik. "Estrogen-like and antioxidant properties of resveratrol in clinical pharmacology and therapeutic use." Akusherstvo i ginekologiia 12_2021 (December 24, 2021): 37–48. http://dx.doi.org/10.18565/aig.2021.12.37-48.
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Acharya, Asha, Ila Das, Des Chandhok, and Tapas Saha. "Redox Regulation in Cancer: A Double-edged Sword with Therapeutic Potential." Oxidative Medicine and Cellular Longevity 3, no. 1 (2010): 23–34. http://dx.doi.org/10.4161/oxim.3.1.10095.
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Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of reactive oxygen species (ROS) and cell’s own antioxidant defenses. ROS deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis. Ultraviolet (UV) exposures, γ-radiation and other environmental carcinogens generate ROS in the cells, which can exert apoptosis in the tumors, thereby killing the malignant cells or induce the progression of the cancer growth by blocking cellular defense system. Cancer stem cells take the advantage of the aberrant redox system and spontaneously proliferate. Oxidative stress and gene-environment interactions play a significant role in the development of breast, prostate, pancreatic and colon cancer. Prolonged lifetime exposure to estrogen is associated with several kinds of DNA damage. Oxidative stress and estrogen receptor-associated proliferative changes are suggested to play important roles in estrogen-induced breast carcinogenesis. BRCA1, a tumor suppressor against hormone responsive cancers such as breast and prostate cancer, plays a significant role in inhibiting ROS and estrogen mediated DNA damage; thereby regulate the redox homeostasis of the cells. Several transcription factors and tumor suppressors are involved during stress response such as Nrf2, NFκB and BRCA1. A promising strategy for targeting redox status of the cells is to use readily available natural substances from vegetables, fruits, herbs and spices. Many of the phytochemicals have already been identified to have chemopreventive potential, capable of intervening in carcinogenesis.
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Compston, Juliet E. "Sex Steroids and Bone." Physiological Reviews 81, no. 1 (January 1, 2001): 419–47. http://dx.doi.org/10.1152/physrev.2001.81.1.419.
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Sex steroids are essential for skeletal development and the maintenance of bone health throughout adult life, and estrogen deficiency at menopause is a major pathogenetic factor in the development of osteoporosis in postmenopausal women. The mechanisms by which the skeletal effects of sex steroids are mediated remain incompletely understood, but in recent years there have been considerable advances in our knowledge of how estrogens and, to a lesser extent androgens, influence bone modeling and remodeling in health and disease. New insights into estrogen receptor structure and function, recent discoveries about the development and activity of osteoclasts, and lessons learned from human and animal genetic mutations have all contributed to increased understanding of the skeletal effects of estrogen, both in males and females. Studies of untreated and treated osteoporosis in postmenopausal women have also contributed to this knowledge and have provided unequivocal evidence for the potential of high-dose estrogen therapy to have anabolic skeletal effects. The development of selective estrogen receptor modulators has provided a new approach to the prevention of osteoporosis and other major diseases of menopause and has implications for the therapeutic use of other steroid hormones, including androgens. Further elucidation of the mechanisms by which sex steroids affect bone thus has the potential to improve the clinical management not only of osteoporosis, both in men and women, but also of a number of other diseases related to sex hormone status.
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Benagiano, Giuseppe, and Ivo Brosens. "The Endometrium in Adenomyosis." Women's Health 8, no. 3 (May 2012): 301–12. http://dx.doi.org/10.2217/whe.12.8.
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Eutopic and ectopic endometria of women with adenomyosis show a series of metabolic and molecular abnormalities that increase angiogenesis and proliferation, decrease apoptosis, allow local production of estrogens, create progesterone resistance, and impair cytokine expression. These changes enhance the ability of the endometrium to infiltrate the junctional zone myometrium and the growth of ectopic tissue. In addition, in these subjects several immunological abnormalities have been observed, together with an increased production of ‘free radicals’ leading to excessive growth of endometrial stromal cells that may facilitate the establishment of adenomyosis. A limiting factor is that these studies have been performed on hysterectomy specimens representing final stages of the disease. This increased knowledge has created new therapeutic options, including the block of local aromatase production through the use of selective estrogen receptor modulators, estrogen-progestin combinations and gonadotropin-releasing hormone super agonists. Also promising are investigations into the mechanism of dysmenorrhea and abnormal uterine bleeding.
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Velez, Maria A., Timothy F. Burns, and Laura P. Stabile. "The estrogen pathway as a modulator of response to immunotherapy." Immunotherapy 11, no. 13 (September 2019): 1161–76. http://dx.doi.org/10.2217/imt-2019-0024.
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Lung cancer is the leading cause of cancer deaths worldwide, with a 5-year survival rate of about 18%. Thus, there is a great need for novel therapeutic approaches to treat non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have improved outcomes for a subset of patients, especially those with high programmed death-ligand 1 expression and/or high tumor mutational burden, but have failed in the majority of patients. Increasing evidence suggests that the estrogen signaling pathway may be a therapeutic target in metastatic NSCLC and that the estrogen pathway may play a role in sex-based responses to ICIs. This report will review the epidemiologic, preclinical and clinical data on the estrogen pathway in NSCLC, its implications in sex-based responses to ICIs and the potential use of antiestrogen therapy in combination with ICIs.
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Kuznetsova, I. V. "Transition period of estrogen-progestogen hormone therapy." Medical alphabet 3, no. 25 (November 19, 2019): 6–10. http://dx.doi.org/10.33667/2078-5631-2019-3-25(400)-6-10.
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Combined hormonal contraception is an effective method of preventing pregnancy and at the same time has a number of therapeutic effects. The need for contraception persists until the final cessation of menstrual function, but at an older fertile age, the selection of a hormonal agent becomes a daunting task. Over the past years, a woman has accumulated factors that can complicate the use of hormonal drugs, and, on the other hand, new problems arise in the transitional period of life, which combined contraceptives can solve. An equally relevant topic is the question of stopping the use of combined hormonal contraceptives and initiating menopausal hormone therapy. All of the above aspects of the use of hormonal drugs require deep understanding for the adequate management of women entering the final phase of reproductive life.
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Biggar, Robert J. "Molecular Pathways: Digoxin Use and Estrogen-Sensitive Cancers—Risks and Possible Therapeutic Implications: Figure 1." Clinical Cancer Research 18, no. 8 (February 24, 2012): 2133–37. http://dx.doi.org/10.1158/1078-0432.ccr-11-1389.
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Zhao, Hong, Ling Zhou, Anna Junjie Shangguan, and Serdar E. Bulun. "Aromatase expression and regulation in breast and endometrial cancer." Journal of Molecular Endocrinology 57, no. 1 (July 2016): R19—R33. http://dx.doi.org/10.1530/jme-15-0310.
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Long-term exposure to excess estrogen increases the risk of breast cancer and type 1 endometrial cancer. Most of the estrogen in premenopausal women is synthesized by the ovaries, while extraovarian subcutaneous adipose tissue is the predominant tissue source of estrogen after menopause. Estrogen and its metabolites can cause hyperproliferation and neoplastic transformation of breast and endometrial cells via increased proliferation and DNA damage. Several genetically modified mouse models have been generated to help understand the physiological and pathophysiological roles of aromatase and estrogen in the normal breast and in the development of breast cancers. Aromatase, the key enzyme for estrogen production, is comprised of at least ten partially tissue-selective and alternatively used promoters. These promoters are regulated by distinct signaling pathways to control aromatase expression and estrogen formation via recruitment of various transcription factors to theircis-regulatory elements. A shift in aromatase promoter use from I.4 to I.3/II is responsible for the excess estrogen production seen in fibroblasts surrounding malignant epithelial cells in breast cancers. Targeting these distinct pathways and/or transcription factors to modify aromatase activity may lead to the development of novel therapeutic remedies that inhibit estrogen production in a tissue-specific manner.
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Foster, Paul A., L. W. Lawrence Woo, Barry V. L. Potter, Michael J. Reed, and Atul Purohit. "The Use of Steroid Sulfatase Inhibitors as a Novel Therapeutic Strategy Against Hormone-Dependent Endometrial Cancer." Endocrinology 149, no. 8 (May 1, 2008): 4035–42. http://dx.doi.org/10.1210/en.2008-0223.
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The past few years have seen an increase in the reported incidence of endometrial carcinoma, one of the most frequently diagnosed malignancies of the female genital tract. Estrogen production is vital for the mitogenesis of endometrial tumors. Inhibition of steroid sulfatase (STS), an enzyme responsible for the synthesis of steroids with estrogenic properties, may represent a novel therapeutic target for this type of cancer. This study investigates the effects of STX64 (also known as 667Coumate and BN83495) and STX213, two potent STS inhibitors, on hormone-dependent endometrial cancer cell growth in vivo. When tested in intact mice with endometrial cancer xenografts, STX64 had limited effect on tumor growth. In contrast, the microtubule disruptor STX140 reduced tumor growth by 55%. In a hormone-dependent endometrial xenograft model in ovariectomized mice, both STX64 and STX213 given orally, daily at 1 mg/kg significantly inhibited tumor growth by 48 and 67%, respectively. However, when given orally at 1 mg/kg once weekly, only STX213 still inhibited tumor proliferation. At a higher dose of STX64 (10 mg/kg, orally, daily), a greater tumor growth inhibition of 59% was observed. Liver and tumor STS activity was completely inhibited in all daily treatment groups. Plasma estradiol (E2) levels were also significantly decreased. A significant correlation was observed between plasma E2 concentrations and STS activity, indicating the importance of circulating E2 on tumor growth. This novel study demonstrates for the first time that STS inhibitors are potent inhibitors of endometrial cancer growth in nude mice.
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Zhao, Liqin, Zisu Mao, and Roberta Diaz Brinton. "A Select Combination of Clinically Relevant Phytoestrogens Enhances Estrogen Receptor β-Binding Selectivity and Neuroprotective Activities in Vitro and in Vivo." Endocrinology 150, no. 2 (February 1, 2009): 770–83. http://dx.doi.org/10.1210/en.2008-0715.
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We have previously shown that a number of naturally occurring phytoestrogens and derivatives were effective to induce some measures of neuroprotective responses but at a much lower magnitude than those induced by the female gonadal estrogen 17β-estradiol. In the present study, we sought to investigate whether a combination of select phytoestrogens could enhance neural responses without affecting the reproductive system. We performed a range of comparative analyses of the estrogen receptor (ER) α/β binding profile, and in vitro to in vivo estrogenic activities in neural and uterine tissues induced by clinically relevant phytoestrogens: genistein, daidzein, equol, and IBSO03569, when used alone or in combination. Our analyses revealed that both the ERα/β binding profile and neural activities associated with individual phytoestrogens are modifiable when used in combination. Specifically, the combination of genistein plus daidzein plus equol resulted in the greatest binding selectivity for ERβ and an overall improved efficacy/safety profile when compared with single or other combined formulations, including: 1) an approximate 30% increase in ERβ-binding selectivity (83-fold over ERα); 2) a greater effect on neuronal survival against toxic insults in primary neurons; 3) an enhanced activity in promoting neural proactive defense mechanisms against neurodegeneration, including mitochondrial function and β-amyloid degradation; and 4) no effect on uterine growth. These observations suggest that select phytoestrogens in combination have the therapeutic potential of an alternative approach to conventional estrogen therapy for long-term safe use to reduce the increased risk of cognitive decline and neurodegenerative disease associated with menopause in women. A combination of genistein, daidzein, and equol enhances estrogen receptor β-binding selectivity and estrogenic activities in promoting neuronal survival and brain defense mechanisms without impact on uterine growth.
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Kuznetsova, I. V., L. V. Evsyukova, and V. A. Konovalov. "Combined oral contraception: is there a resource for increased use?" Medical Council, no. 12 (July 29, 2018): 146–51. http://dx.doi.org/10.21518/2079-701x-2018-12-146-151.
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Combined oral contraceptives (COCs) are a highly effective method for preventing unintended pregnancy, but unfortunately, the resource of their contraceptive and therapeutic potential is not used enough, and global unintended pregnancies account for about 40%. The reasons for the lack of proper distribution of COCs are insufficient awareness of the beneficial properties of contraception, along with exaggerated fears of the adverse effects of hormone intake both among women and among doctors. This problem can only be overcome by providing adequate information to health professionals regarding the accumulated data and bringing this information to potential users. The review examines the risks of possible complications, as well as the preventive and therapeutic benefits of some COCs. The COC group is represented by preparations, which properties may differ significantly due to the different dose of the estrogen component and the qualitative characteristics of the progestins. Despite the launch of new combination drugs, COCs deserve high attention. Their efficacy and safety is confirmed by the long practical administration.
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Gucalp, Ayca, and Tiffany A. Traina. "Triple-Negative Breast Cancer: Adjuvant Therapeutic Options." Chemotherapy Research and Practice 2011 (June 21, 2011): 1–13. http://dx.doi.org/10.1155/2011/696208.
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Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2(HER2) represents 15% of all breast cancers. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Furthermore, this subtype accounts for a disproportionate number of disease-related mortality in part due to its aggressive natural history and our lack of effective targeted agents beyond conventional cytotoxic chemotherapy. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents.
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Hahn, S. E., L. A. da Cruz, D. Sayegh, A. Ferry, K. O’Reilly, D. S. Pereira, D. B. Rubinstein, H. Findlay, and D. S. Young. "Therapeutic monoclonal antibodies target phenotypically-differing human breast cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 13510. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.13510.
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13510 Background: CD44 (an adhesion molecule and stem cell antigen), CD59 (a complement-inhibitory molecule), MCSP (an adhesion and cell-cell interactions), and Trop-2 (EpCam a related signaling molecule) represent a group of biologically-significant cancer proteins acting through distinct mechanisms. We have described Abs with in vitro and in vivo cancer suppressive activity to this group of targets. However, their effectiveness depends on the phenotype of malignant cells; cell response should correlate with expression of its Ag, and tumor cells represent a heterogeneous group of non-synchronous cells. The present study describes the efficacy of those antibodies in breast cancer models and the prevalence of their antigen targets in a survey of human breast cancer tissues. Methods: In vivo activity of antibodies ARH460–16–2 (anti-CD44), AR36A36.11.1 (anti-CD59), AR11BD-2E11–2 (anti-MCSP), and AR47A6.4.2 (anti-Trop-2) in estrogen-dependent and hormone sensitive xenograft models of human breast cancer was examined. In addition, distribution of the antigens in breast cancer was determined by immunohistochemistry using tumor tissue arrays of breast cancer sections from distinct patients. Results: Treatment of an established breast cancer model with ARH460–16–2 resulted in 51% median tumor xenograft suppression (p<0.05), as well as increased survival in an MDA-MB-231 (breast cancer) grafted model. 63% of human breast cancer sections expressed the CD44 antigen. Treatment with anti-CD59 antibody AR36A36.11.1 resulted in 68% xenograft tumor suppression (p<0.005). AR47A6.4.2 anti-Trop-2 antibody bound to 100% of human breast cancer sections tested, and showed efficacy in the estrogen- dependent MCF-7 breast cancer model. Anti-MCSP antibody AR11BD-2E11–2 demonstrated 80% tumor growth inhibition (p<0.001), increased survival in an estrogen-dependent model of breast cancer, and was found to stain 62% of breast cancer tissues examined. Conclusions: The heterogeneity of breast cancer cell phenotypes in in vitro and in vivo studies and variable composite cellular antigen targets is the basis for the therapeutic use of multiple antibodies, each with independent mechanisms of action, and offers a rationale for combined antibody therapy in selected patients. [Table: see text]
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Monaco, Alessandra, Fabrizio Licitra, Martina Di Gisi, Giovanni Galasso, Marzia Di Donato, Pia Giovannelli, Antimo Migliaccio, and Gabriella Castoria. "ERβ in Triple-Negative Breast Cancer: Emerging Concepts and Therapeutic Possibilities." Endocrines 2, no. 3 (September 13, 2021): 356–65. http://dx.doi.org/10.3390/endocrines2030033.
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Despite the improvements in diagnostic and therapeutic approaches, breast cancer still remains one of the world’s leading causes of death among women. Particularly, triple negative breast cancer (TNBC) is characterized by aggressiveness, metastatic spreading, drug resistance and a very high percentage of death in patients. Nowadays, identification of new targets in TNBC appears very compelling. TNBC are considered negative for the estrogen receptor alpha (ERα) expression. Nevertheless, they often express ERβ and its variants. As such, this TNBC subtype still responds to estrogens. While the ERβ1 variant seems to act as a tumor-suppressor, the two variants ERβ2 and 5 exhibit pro-oncogenic activities in TNBC. Thus, ERβ1 activation might be used to limit the growth and spreading as well as to increase the drug sensitivity of TNBC. In contrast, the pro-oncogenic properties of ERβ2 and ERβ5 suggest the possible development and clinical use of specific antagonists in TNBC treatment. Furthermore, the role of ERβ might be regarded in the context of the androgen receptor (AR) expression, which represents another key marker in TNBC. The relationship between AR and ERβ as well as the ability to modulate the receptor-mediated effects through agonists/antagonists represent a challenge to develop more appropriate therapies in clinical management of TNBC patients. In this review, we will discuss the most recent data in the field. Therapeutic implications of these findings are also presented in the light of the discovery of specific ERβ modulators.
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shen, Tian, Helia Nasrollahi Sanchez, Hong Zan, and Paolo Casali. "Short-chain fatty acid HDAC inhibitor-mediated downregulation of AID expression and class switch DNA recombination is relieved by estrogen through modulation of selected microRNAs." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 127.12. http://dx.doi.org/10.4049/jimmunol.196.supp.127.12.
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Abstract Estrogen contributes to the elevated antibody response to vaccines in women and the female bias of autoimmune responses, likely by increasing class-switched and hypermutated antibodies and pathogenic autoantibodies. As we have shown, estrogen potentiates the induction of AID, which is critical for class switch DNA recombination (CSR) and somatic hypermutation (SHM), through upregulation of HoxC4. Estrogen may also alter AID gene expression through epigenetic modifications. As we have also shown, short-chain fatty acid (SCFA) histone deacetylase inhibitors (HDIs), including valproic acid and butyrate, upregulated miRNAs that silence AID expression, resulted in reduction of T-dependent and T-independent antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone mice. Here we found that the HDI-mediated downregulation of antibody and autoantibody responses was reversed by estrogen but significantly enhanced by deletion or inhibition of estrogen receptor α (ERα). In B cells, estrogen downregulated the expression of miR-26a, which we found to target the 3′UTR Aicda mRNA. miR-26a was highly expressed in activated B cells and significantly upregulated by SCFA HDIs. Estrogen enhanced cytoplasm to nuclear translocation of HDAC4/HDAC5, and decreased histone acetylation of the host gene of miR-26, and possibly, other selective miRNAs. Finally, The estrogen-mediated enhancement of AID was abrogated by selective inhibition of HDAC4/HDAC5 by LMK258, which decreased CSR. Collectively, our findings provide mechanistic insights into the immunomodulating activity of estrogen and its potential use as therapeutic target in systemic autoimmunity. Supported by the NIH grants AI 105813, AI 079705.
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Cannataro, Roberto, and Erika Cione. "Nutritional Supplements and Lipedema: Scientific and Rational Use." Nutraceuticals 2, no. 4 (October 3, 2022): 270–77. http://dx.doi.org/10.3390/nutraceuticals2040020.
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Lipedema is a pathology of the adipose tissue, in evident female prevalence, diagnosed clinically and still of not well-defined etiopathogenesis. Indeed, an estrogen-related component is present, and an inflammatory state and a condition of edema are present in most cases; even pain seems to be a recurring feature, and insulin resistance is also often associated with lipedema. The therapeutic approach is finally becoming holistic. Therefore, with surgery, physiotherapy, and elastic compression therapy, the nutritional aspect of food supplementation is gaining much value. The objective of the present work is to consider the nutritional supplements that could be useful to manage this condition, underlining that, at the moment, the specific literature is practically non-existent. The most promising supplements seem to be omega 3 fish oil, polyphenols, and vitamin C, but the need for studies in this sector is urgent.
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Kim, Kyung Hee, Derek Toomre, and Jeffrey R. Bender. "Splice isoform estrogen receptors as integral transmembrane proteins." Molecular Biology of the Cell 22, no. 22 (November 15, 2011): 4415–23. http://dx.doi.org/10.1091/mbc.e11-05-0416.
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In addition to enhancing or repressing transcription, steroid hormone receptors rapidly transduce kinase activation signals. On ligand engagement, an N-terminus–truncated splice isoform of estrogen receptor (ER) α, ER46, triggers membrane-initiated signals, resulting in endothelial nitric oxide synthase (eNOS) activation and endothelial NO production. The orientation of ER46 at the plasma membrane is incompletely defined. With the use of ecliptic pHluorin-fused ER46, total internal reflection fluorescence microscopy in live human endothelial cells illustrates that ER46 can topologically conform to a type I transmembrane protein structure. Mutation of isoleucine-386 at the center of ER46's transmembrane hydrophobic core prevents membrane spanning, obscures the N-terminal ectodomain, and effects a marked reduction in membrane-impermeant estrogen binding with diminished rapid eNOS activation and NO production, despite maintained genomic induction of an estrogen response element–luciferase reporter. Thus there exist pools of transmembrane steroid hormone receptors that are efficient signaling molecules and potential novel therapeutic targets.
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Chen, Shuhua, Jon Nilsen, and Roberta Diaz Brinton. "Dose and Temporal Pattern of Estrogen Exposure Determines Neuroprotective Outcome in Hippocampal Neurons: Therapeutic Implications." Endocrinology 147, no. 11 (November 1, 2006): 5303–13. http://dx.doi.org/10.1210/en.2006-0495.
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To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17β-estradiol (E2) exposure were developed and used to assess the neuroprotective efficacy of E2 against β-amyloid-1–42 (Aβ1–42)-induced neurodegeneration in rat primary hippocampal neurons. Low E2 (10 ng/ml) exposure exerted neuroprotection in each of the perimenopausal temporal patterns, acute, continuous, and intermittent. In contrast, high E2 (200 ng/ml) was ineffective at inducing neuroprotection regardless of temporal pattern of exposure. Although high E2 alone was not toxic, neurons treated with high-dose E2 resulted in greater Aβ1–42-induced neurodegeneration. In prevention vs. treatment simulations, E2 was most effective when present before and during Aβ1–42 insult. In contrast, E2 treatment after Aβ1–42 exposure was ineffective in reversing Aβ-induced degeneration, and exacerbated Aβ1–42-induced cell death when administered after Aβ1–42 insult. We sought to determine the mechanism by which high E2 exacerbated Aβ1–42-induced neurodegeneration by investigating the impact of low vs. high E2 on Aβ1–42-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E2 significantly prevented Aβ1–42-induced rise in intracellular calcium, whereas high E2 significantly increased intracellular calcium and did not prevent Aβ1–42-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E2 exposure before, but not after, Aβ1–42-induced neurodegeneration. These data are relevant to impact of perimenopausal E2 exposure on protection against neurodegenerative insults and the use of estrogen therapy to prevent vs. treat Alzheimer’s disease. Furthermore, these data are consistent with a healthy cell bias of estrogen benefit.
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Yukalchuk, D. Yu, D. M. Ponomarenko, T. N. Yukalchuk, S. S. Sidorova, A. V. Shevchuk, and A. M. Novopashin. "The Use of Alpelisib in Metastatic Estrogen-Receptor-Positive HER2/Neu-Negative Breast Cancer." Effective Pharmacotherapy 18, no. 13 (April 25, 2022): 121–16. http://dx.doi.org/10.33978/2307-3586-2022-18-13-12-16.
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The clinical case presented in the article demonstrates the effectiveness of orange in combination with fulvestrant in metastatic estrogen receptor-positive HER2/neu-negative breast cancer with a mutation in the PIK3CA gene. The resistance of hormone therapy requires the search for new therapeutic options. The results of the SOLAR-1 and BYLieve studies have shown not only the effectiveness of alpelisib, but also new types of toxicity characteristic of this therapy. At the moment, recommendations have been developed for the prevention and treatment of the most frequent adverse events, allowing the drug to be used as safely as possible. With the introduction of alpelisib, the possibilities of non-chemotherapeutic treatment options for prognostically unfavorable patients have not only expanded, but there has also been a trend towards the use of personalized medicine and targeted therapy.
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Oualla, Karima, Heba M. El-Zawahry, Banu Arun, James M. Reuben, Wendy A. Woodward, Heba Gamal El-Din, Bora Lim, Nawfel Mellas, Naoto T. Ueno, and Tamer M. Fouad. "Novel therapeutic strategies in the treatment of triple-negative breast cancer." Therapeutic Advances in Medical Oncology 9, no. 7 (June 13, 2017): 493–511. http://dx.doi.org/10.1177/1758834017711380.
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Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is defined by negative estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Treating patients with TNBC remains clinically challenging, as patients are not candidates for endocrine or HER2-directed therapy. As a result, chemotherapy with traditional agents such as anthracyclines and taxanes remains the only available option with moderate success. Recent discoveries have revealed that TNBC is a heterogeneous disease at the clinical, histological and molecular levels. The use of biomarkers to identify distinct subsets of TNBC that derive the greatest benefit from presently approved as well as novel therapeutics has become the main focus of current research. The aim of this review is to explore the clinical and biological complexity of TNBC as well as identify novel therapeutic options that target the various molecular subsets of TNBC.
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Bitirim, Ceylan V., Zeynep B. Ozer, and Kamil C. Akcali. "Estrogen receptor alpha regulates the expression of adipogenic genes genetically and epigenetically in rat bone marrow-derived mesenchymal stem cells." PeerJ 9 (September 10, 2021): e12071. http://dx.doi.org/10.7717/peerj.12071.
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Regulation of the efficacy of epigenetic modifiers is regarded as an important control mechanism in the determination and differentiation of stem cell fate. Studies are showing that the effect of estrogen is important in the differentiation of mesenchymal stem cells (MSCs) into adipocytes, osteocytes, and chondrocytes. Activation of certain transcription factors and epigenetic modifications in related genes play an active role in the initiation and completion of adipogenic differentiation. Understanding the role of estrogen in diseases such as obesity, which increases with the onset of menopause, will pave the way for more effective use of estrogen as a therapeutic option. Demonstration of the differentiation tendencies of MSCs change in the presence/absence of estrogen, especially the evaluation of reversible epigenetic changes, will provide valuable information for clinical applications. In this study, the effect of estrogen on the expression of genes involved in adipogenic differentiation of MSCs and accompanying epigenetic modifications was investigated. Our results showed that estrogen affects the expression of adipogenesis-related transcription factors such as PPARy, C/EBPα and Adipsin. In addition, after estrogen treatment, increased accumulation of estrogen receptor alpha (ERα) and repressive epigenetic markers such as H3K27me2 and H3K27me3 were observed on the promoter of given transcription factors. By using co-immunoprecipitation experiments we were also able to show that ERα physically interacts with the zeste homolog 2 (EZH2) H3K27 methyltransferase in MSCs. We propose that the increase of H3K27me2 and H3K27me3 markers on adipogenic genes upon estrogen treatment may be mediated by the direct interaction of ERα and EZH2. Taken together, these findings suggest that estrogen has a role as an epigenetic switcher in the regulation of H3K27 methylation leading to suppression of adipogenic differentiation of MSC.
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Ghuge, Rahul B., Prashant R. Murumkar, Kailash M. Choudhary, Karan D. Joshi, Monica Chauhan, Rahul R. Barot, and Mange R. Yadav. "Development of Steroidal Aromatase Inhibitors as Potential Anti-breast Cancer Agents." Current Enzyme Inhibition 16, no. 1 (May 4, 2020): 45–62. http://dx.doi.org/10.2174/1573408016666200212094804.
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Breast cancer is the most prevalent type of cancer and one of the leading causes of death among all the cancers affecting women worldwide. Preliminary cause of development of tumors in the breast cancer in post-menopausal women is mostly the increased estrogen levels in the body which could be the result of overexpression of aromatase CYP450 i.e. CYP19A1. Aromatase is the only enzyme present in humans that brings about aromatization of A-ring of 19-carbon androgens to form 18-carbon estrogens. Inhibiting aromatase enzyme thereby decreasing the estrogen levels in the postmenopausal women has been considered as an important strategy for the management of breast cancer. Three generations of aromatase inhibitors including steroidal viz. testolactone, formestane, exemestane and non-steroidal viz. aminoglutethimide, fadrozole, letrozole, anastrozole, the two classes of drugs have been approved for clinical use for the treatment of breast cancer. A large number of research and review articles have been reported so far describing the therapeutic efficacy of steroidal and non-steroidal aromatase inhibitors. However, steroidal aromatase inhibitors, being more selective inhibitors and having certain other advantages, overruled the discovery of novel aromatase inhibitors compared to the non-steroidal aromatase inhibitors which lack selectivity for CYP450 aromatase. In this review, efforts have been made to describe the developments of steroidal aromatase inhibitors to date.
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Downs, William V., Edward L. Perkins, William E. Burak, and Himangshu S. Bose. "ODP433 An increased in AIPB expression in Triple Negative (ER-/PR-/Her2-) Breast Tumors reduces estradiol synthesis." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A671. http://dx.doi.org/10.1210/jendso/bvac150.1388.
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Abstract Aromatase (estrogen synthetase) is a p450 family of enzymes that catalyzes testosterone to estradiol in presence of a cofactor NADPH. Aromatase is central for its role in reproduction and reproductive diseases for catalyzing the conversion of testosterone to estradiol by aromatase. Since aromatase is responsible for the synthesis of estrogens, it is essentially a rate limiting enzyme. Aromatase is expressed mainly in the ovaries of premenopausal women and placentas of pregnant women. Therapeutic approaches for controlling breast cancer proliferation include reducing estrogen by interfering with its production via ovarian ablation in premenopausal women and/or use of aromatase inhibitors or inactivators in postmenopausal women. The use of aromatase inhibitors can lead to rapid drug resistance and refractory disease. In triple negative breast cancers (TNBC) aromatase expression remains undetectable. Therefore, treatment of TNBC remains a challenge to the patients resulting in premature and very early death. Our laboratory is investigating the role of Aromatase Interacting Partner in Breast (AIPB), in TNBC cells (MDA-MB-231 cells). AIPB is a 22 kDa protein, present partially in the MAM (Mitochondria Associated-ER Membrane) but mainly in the endoplasmic reticulum associated with aromatase in the unaffected human breast tissue. The AIPB localization in the organelle was determined biochemically and visualized through scanning electron microscopy (SEM). We have cloned AIPB in a tetracycline inducible expression system (pTETOneAIPB) and created on demand expression of AIPB in MDA-MB-231 cells. In pTETOneAIPB engineered MDA-MB-231 cells addition of doxycycline resulted in a several fold increase in AIPB expression as compared to uninduced or MDA-MB-231 cells by quantitative PCR analysis. The growth rate of pTETOneAIPB is almost five-fold slower than the MBA-MB-231 cells. Interestingly estradiol synthesis was also decreased following doxycycline addition measured through radioimmuno assay (RIA). Therefore, our results suggest that restoration of AIPB expression may potentially reduce estradiol synthesis in TNBC patients and provide an additional therapeutic approached to treatment. Presentation: No date and time listed
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Wu, Malinda, Neha Arora, Viranuj Sueblinvong, William R. Hunt, and Vin Tangpricha. "Estrogen Supplementation Is Associated With Higher Quality of Life Scores in Women With Cystic Fibrosis." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A732. http://dx.doi.org/10.1210/jendso/bvab048.1489.
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Abstract Purpose: With rapid advancements in therapeutic options for patients with cystic fibrosis (CF), the median predicted survival has increased to 47 years along with the prevalence of non-pulmonary complications for patients with CF. Women with CF suffer irregular menses, sexual dysfunction and low bone mineral density. With increasing pregnancies among women with CF, they may consider contraception. Estrogen supplementation may modulate these outcomes and others. The purpose of this study was to explore the effects of supplemental estrogen use on quality of life (QOL) in CF. Methods: Women with CF ages 16-50 years were administered a validated CF-specific QOL survey (CFQ-R) during a routine CF clinic visit through an IRB-approved cross-sectional study. The QOL domain scores of subjects taking and not taking estrogen were compared pairwise by Kruskal Wallis tests and overall by Wilcoxon signed rank test. Results: The estrogen exposed and estrogen unexposed subjects with CF had similar age, BMI, FEV1, race, CF mutation, pancreatic insufficiency, diabetes and relationship status. The estrogen exposed subjects were taking 20-30 mcg of ethinyl estradiol in oral contraceptive pills. The estrogen exposed subjects had consistently higher QOL scores than the estrogen unexposed subjects (p=0.001). The estrogen exposed subjects had significantly higher scores in 7 of the 12 CFQ-R categories: physical, vitality, treatment burden and role domains and weight, respiratory and digestion symptom scales (p<0.05). When correcting for multiple comparisons, the estrogen-supplemented women had higher role domain scores than women not taking estrogen supplement (p=0.03). Conclusions: Estrogen supplementation was associated with improved quality of life in women with CF. This cross-sectional study highlights the need for further investigation into the potential benefits of estrogen supplementation. The dose, route, formulation and timing of estrogen therapy may modulate the beneficial effects for women with CF. Support: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award TL1TR002382 and UL1TR002378, and Cystic Fibrosis Foundation award WU20D0. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or CFF.
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Vorobiof, Daniel A. "Recent advances in the medical treatment of breast cancer." F1000Research 5 (November 29, 2016): 2786. http://dx.doi.org/10.12688/f1000research.9619.1.
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Over the past few decades, the systemic therapy of breast cancer (early and advanced) has changed considerably. For the past 40–50 years, and since the discovery and further therapeutic use of tamoxifen, a selective estrogen receptor modulator, breast cancer treatment has become the model for the development and success of tailored medical treatment. Much still needs to be done in improving outcomes for all patients with breast cancer, and especially for those who have advanced breast cancer, a challenging area for medical oncologists. Ongoing international clinical trials are currently evaluating new therapeutic approaches and identifying specific biological subsets that could determine a patient’s ability to respond to particular chemotherapeutic drugs.
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Gunther, Jillian R., Yuhong Du, Eric Rhoden, Iestyn Lewis, Brian Revennaugh, Terry W. Moore, Sung Hoon Kim, Raymond Dingledine, Haian Fu, and John A. Katzenellenbogen. "A Set of Time-Resolved Fluorescence Resonance Energy Transfer Assays for the Discovery of Inhibitors of Estrogen Receptor-Coactivator Binding." Journal of Biomolecular Screening 14, no. 2 (February 2009): 181–93. http://dx.doi.org/10.1177/1087057108329349.
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Therapeutic block of estrogen action is typically achieved with conventional antagonists (CAs), compounds that displace estradiol from the estrogen receptor (ER) and induce formation of an ER conformation that cannot bind to coactivator proteins, such as the steroid receptor coactivators (SRCs). As an alternative mode for blocking estrogen action, the authors seek small molecules that act as coactivator binding inhibitors (CBIs)—that is, they compete directly with SRC3 for interaction with estradiol-bound ER. CBIs would be interesting mechanistic probes of estrogen action and might also provide an alternative, more durable endocrine therapy for hormone-responsive breast cancer, where cellular adaptations lead to resistance to CAs. The authors have designed and optimized a set of time-resolved fluorescence resonance energy transfer (TR-FRET) assays to monitor the interaction of ER with SRC3 and ligands, and they have used them in high-throughput screens to discover small-molecule CBIs that are able to disrupt this interaction. These assays also distinguish CBIs from CAs. These robust and sensitive “mix-and-measure” assays use low concentrations of ER labeled with a europium chelate as FRET donor and a Cy5-labeled SRC as acceptor. This multiplexed protocol produces excellent signal-to-noise ratios (>100) and Z′ values (>0.8). ( Journal of Biomolecular Screening 2009:181-193)
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Li, Ang. "An Overview of Tumor Necrosis Factor-α on Pathophysiological Mechanisms, Relevant Therapeutic Status in Breast Cancer." Highlights in Science, Engineering and Technology 8 (August 17, 2022): 472–80. http://dx.doi.org/10.54097/hset.v8i.1201.
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TNFα is an essential pro-inflammatory cytokine that is prevalent in the tumor microenvironment and is involved in mediating or activating many significant signaling pathways which result in inflammation, apoptosis, and tumor cell proliferation, survival, and invasiveness. In breast cancer, TNFα is involved throughout all stages from occurrence, development, procession, and metastasis to recurrence. Researchers have pointed out that TNFα plays a major role in the estrogen biosynthesis pathway, especially in the process of adipose tissue switching to estrogen. In the breast tumor microenvironment, TNFα may participate in the mediation of estrone sulfatase expression and activity. In terms of therapeutics, methods to suppress TNFα signaling in breast cancer have been proposed. To neutralize the pro-tumor and inflammatory effects of TNFα, most research opts to use anti-TNFα antibodies. According to the research, the administration of TNFα antagonists can suppress the development of breast cancer cells and strengthen the chemotherapeutic response when used as adjuvant therapy with chemotherapy. Consequently, tumor drug resistance can be well controlled. However, some side effects like systemic toxicity, the typical skin lesion, and the increasing risk of developing new cancers are still major issues. More extensive clinical trials have to be carried out for deeper investigation. This paper gives an overview of the intrinsic features of TNFα as a cytokine and gets insight into the pathophysiological mechanisms mediated by TNFα in breast cancer. Furthermore, the current state of knowledge in terms of TNF-related therapeutic strategies was adequately summarized and discussed.
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Ray, Rinki, Christine M. Herring, Troy A. Markel, Paul R. Crisostomo, Meijing Wang, Brent Weil, Tim Lahm, and Daniel R. Meldrum. "Deleterious effects of endogenous and exogenous testosterone on mesenchymal stem cell VEGF production." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 294, no. 5 (May 2008): R1498—R1503. http://dx.doi.org/10.1152/ajpregu.00897.2007.
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Modulating the paracrine effects of bone marrow mesenchymal stem cells (BMSCs) may be important for the treatment of ischemic myocardial tissue. In this regard, endogenous estrogen may enhance BMSC vascular endothelial growth factor (VEGF) production. However, little information exists regarding the effect of testosterone on stem cell function. We hypothesized that 1) endogenous or exogenous estrogen will enhance stem cell production of VEGF and 2) endogenous or exogenous testosterone will inhibit BMSC VEGF production. BMSCs were collected from adult male, female, castrated male, and ovariectomized female rats. One hundred thousand cells were incubated with testosterone (1, 10, or 100 nM) or estrogen (0.15, 1.5, or 15 nM) for 48 h. Cell supernatants were collected, and VEGF was measured by ELISA. BMSCs harvested from castrated males, normal females, and ovariectomized females produced more VEGF compared with normal males. Castration was associated with the highest level (1,018 ± 98.26 pg/ml) of VEGF production by BMSCs, which was significantly more than that produced by BMSCs harvested from normal male and normal female animals. Exogenous testosterone significantly reduced VEGF production in BMSCs harvested from ovariectomized females in a dose-dependent manner. Exogenous estrogen did not alter BMSC VEGF production. These findings suggest that testosterone may work on BMSCs to decrease protective growth factor production and that effective removal of testosterone's deleterious effects via castration may prove to be beneficial in terms of protective factor production. By manipulating the mechanisms that BMSCs use to produce growth factors, we may be able to engineer stem cells to produce maximum growth factors during therapeutic use.
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Thabet, Romany H., Adel A. Gomaa, Laila M. Matalqah, and Erin M. Shalaby. "Vitamin D: an essential adjuvant therapeutic agent in breast cancer." Journal of International Medical Research 50, no. 7 (July 2022): 030006052211138. http://dx.doi.org/10.1177/03000605221113800.
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Low serum levels of vitamin D have been reported as a risk factor for breast cancer. This narrative review provides an update on the impact of vitamin D on hormone receptors, notably estrogen receptor subunits, and gives insights on possible therapeutic interventions to overcome breast cancer. In addition, evidence that supports the beneficial use of vitamin D as adjuvant treatment of breast cancer is summarized. Vitamin D deficiency is significantly widespread in patients with triple-negative tumors. Several studies have observed a possible modulatory effect of vitamin D or its analogues on the expression of different hormone receptors in breast cancer and increased sensitivity to tamoxifen. Vitamin D possesses anti-inflammatory and immunomodulatory effects in patients with breast cancer, and the mechanism of action of vitamin D in patients with breast cancer is discussed. In conclusion, vitamin D appears to have a beneficial role in the prevention and management of breast cancer, however, large-scale, randomized controlled trials are needed to confirm the effects of vitamin D in breast cancer prevention or treatment.
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Komal S, Harikrishnan N, Gejalakshmi S, Kayalvizhi S, Hemamalini Baskaran, Priyanka J, Mohan Kumar A, and Sriram GM. "Novel herbs and drugs for endometriosis management: A review on current and futuristic therapies." International Journal of Research in Pharmaceutical Sciences 12, no. 2 (May 8, 2021): 1404–14. http://dx.doi.org/10.26452/ijrps.v12i2.4699.
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A disorder with estrogen dependency comprising of inflammatory lesions outside the uterus, causing pain and inflammation in pelvis and affecting women of reproductive age with infertility and post reproductive age is endometriosis. Endometriosis is viewed as public health issue with a major impact on quality of life of women. Medically advanced computational and chemical treatments are available to treat the progression of the disease by diagnostic imaging, clinical examinations, imaging and laparoscopy often leading to immediate surgery. A warrantable rethinking on the diagnosis and management of endometriosis is to be assessed and medical treatments should be considered as first-line option for therapeutic relief for endometriosis by suppressing the systemic estrogen levels providing desirable efficacy and safety, prior to performing endometriosis surgery. The aim of this review is to describe natural products, hormonal and non-hormonal compounds that suppress the progression of endometriosis. Various herbal, conventional and traditional therapies are investigated to treat gynecological disease, endometriosis. The information in this paper include various studies assessing the use of novel treatments in addition to the herbal and hormonal products in the endometriosis therapy. Most of the studies involved were in scrutinizing the pharmacological activity profiles of various sources of drugs in endometriosis treatment, hormonal drugs involved suppression and regulation of various hormones along with various factors like anti-inflammatory, anti-oxidant, anti-proliferative and apoptotic, anti-angiogenic, anti-invasive, immunomodulatory, and estrogen modulating activity. However, novel drugs and medicinal plants are also reviewed here to draw attention to the molecules of drugs that target at multiple points for rational therapeutic treatment of endometriosis.
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Ciesielska, Aleksandra, Aida Kusiak, Agata Ossowska, and Magdalena Emilia Grzybowska. "Changes in the Oral Cavity in Menopausal Women—A Narrative Review." International Journal of Environmental Research and Public Health 19, no. 1 (December 27, 2021): 253. http://dx.doi.org/10.3390/ijerph19010253.
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Oral health awareness during the menopausal period is essential to minimize the inevitable inconveniences which may occur due to hormonal changes. The decrease in estrogen hormone concentration impacts the oral mucosa in a similar way to the vaginal mucosa due to the presence of estrogen receptors in both of these structures. An estrogen deficiency also affects the maturation process of the oral mucosal epithelium and can lead to its thinning and atrophy, making it more susceptible to local mechanical injuries, causing a change in pain tolerance and problems in the use of removable prosthetic restorations. Mucosal epithelium during the menopausal period is more vulnerable to infections, candidiasis, burning mouth syndrome, oral lichen planus (OLP), or idiopathic neuropathy. Moreover, salivary glands are also hormone-dependent which leads to changes in saliva secretion and its consistency. In consequence, it may affect teeth and periodontal tissues, resulting in an increased risk of caries and periodontal disease in menopausal women. Due to the large variety of complaints and symptoms occurring in the oral cavity, menopausal women constitute a significant group of patients who should receive special preventive and therapeutic care from doctors and dentists in this particular period.
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Yu, Xinge, Angela C. Weyand, and Jordan A. Shavit. "Surprisingly Rapid Onset of Estrogen-Induced Venous Thrombosis in an Animal Model." Blood 132, Supplement 1 (November 29, 2018): 418. http://dx.doi.org/10.1182/blood-2018-99-120325.
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Abstract Venous thrombosis is a well-known complication of sex hormone therapy, with onset typically within weeks to months after initiation. Worldwide, more than 100 million pre-menopausal women use combined oral contraceptives, thus tens to hundreds of thousands develop thrombosis annually, resulting in significant morbidity and mortality. Estrogens are thought to be the major thrombotic risk, although the impact of progestins is less clear. It has been hypothesized that progestin effects may be secondary to mitigation of the estrogen effect. Although it is known that estrogens and progestins can alter expression of coagulation factors, the pathways and mechanisms that connect the two systems, as well as the proteins involved in progression to thrombosis, are poorly understood. Identification of these mediators are central to any comprehensive understanding of hormone-induced pathophysiology, could help ascertain patients at higher risk for thrombosis, and might also pinpoint future therapeutic targets. The zebrafish is a powerful genetic model in which the hemostatic system is nearly entirely conserved with humans. Its external development, ability to generate thousands of offspring at low cost, and optical transparency all make it a powerful tool to study the genetics of coagulation disorders. We previously produced a transgenic line (fabp-fgb-egfp) that generates GFP tagged fibrinogen beta (Fgb), which is incorporated into induced and spontaneous fibrin-rich thrombi. Here we show surprisingly rapid onset of estrogen-induced thrombosis. We exposed 5-6 day old transgenic zebrafish larvae to a range of concentrations of estradiol over 4-24 hours. We discovered green fluorescent deposits co-localizing to the posterior cardinal vein (PCV, orthologous to the inferior vena cava), but not other vessels. This occurred within 4 hours in a dose-dependent fashion. Confocal imaging demonstrated that the fluorescence was intravascular and deposited along the endothelium. Pre-incubation with warfarin and the direct oral anticoagulants rivaroxaban and dabigatran inhibited the fluorescent signal, confirming that the deposits were fibrin thrombi. This phenotype was similar to spontaneous PCV thrombosis observed in zebrafish mutants deficient in antithrombin, which also demonstrate a consumptive coagulopathy with absence of venous occlusion in response to endothelial injury. Therefore we treated 3 dpf larvae with estradiol for 4 hours, followed by laser-mediated endothelial injury and measurement of the time to occlusion (TTO) in the PCV by a blinded observer. Although the median TTO only increased from 12.5 to 15 seconds with treatment, this was highly statistically significant (p=0.0001, Mann Whitney U test, n = 81-98 for each group), consistent with a consumptive coagulopathy. To evaluate the role of progestins, 6 dpf larvae were treated with estradiol and levonorgestrel, desogestrel, or norethisterone, alone or in combination, and quantitatively scored for the presence of thrombosis by a blinded observer. The rates of thrombosis were 72% for estradiol, ranged 15-31% for the progestins, and ranged 66-70% for the combined estrogen/progestin treatments. In summary, our results are nearly identical to loss of antithrombin in zebrafish, although the consumptive coagulopathy is not as potent. These data are consistent with human estrogen-induced venous thromboembolism, but it was completely unexpected and concerning to see the production of thrombi in such a rapid fashion. Our data also suggest that progestins do not mitigate nor potentiate this effect. Future screens using this model are ideally posed to identify the mediators of sex hormone-induced thrombosis, and the results could potentially lead to innovative preventive or therapeutic modalities. Disclosures Shavit: CSL Behring: Consultancy; Octapharma: Consultancy; Shire: Consultancy; Bayer: Consultancy, Research Funding.
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Lopez-Munoz, E., N. Garcia-Hernandez, R. I. Penaloza-Espinosa, M. E. Gomez-Del Toro, G. Zarco-Espinosa, S. Barroso-Bravo, F. Salamanca-Gomez, and D. J. Arenas-Aranda. "”BIK/NBK Gene Expression as a Possible Marker of Circulating Breast Cancer Cells in Blood“." Open Biomarkers Journal 4, no. 1 (October 14, 2011): 8–14. http://dx.doi.org/10.2174/1875318301104010008.
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The detection of circulating breast cancer cells in blood could be of special interest as an indicator of diagnosis and prognosis, and for the selection of treatment. In a previous report, our research group determined gene expression profiles in samples of breast cancer tissue, identifying over-expression of the BIK/NBK mRNA gene in 90% of the analyzed samples. In this paper, we analyze the BIK/NBK gene expression as a possible biomarker of circulating breast cancer cells in blood. We demonstrate that the BIK/NBK gene expression is not a significant biomarker in the detection of circulating breast cancer cells in the blood of women with breast cancer. Several studies have evaluated the regulation of apoptosis by estrogens in breast cancer cells, demonstrating the importance of BIK/NBK protein, in estrogen-regulated breast cancer cell apoptosis, which suggests that the regulation of its expression may be an important therapeutic target or strategy in the management of cancer, and, although we did not find statistically significant differences among the patient groups to demonstrate that BIK/NBK gene expression is a biomarker of circulating breast cancer cells in blood, we consider it necessary to continue the study of this gene in breast cancer tissue and its role in the development and progression of breast cancer, its prognostic value, and its potential use as therapeutic target.