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1
Dickson, S. R., and M. J. Warburton. "Enhanced synthesis of gelatinase and stromelysin by myoepithelial cells during involution of the rat mammary gland." Journal of Histochemistry & Cytochemistry 40, no. 5 (May 1992): 697–703. http://dx.doi.org/10.1177/40.5.1315355.
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During the involution of the mammary gland there is destruction of the basement membrane as the secretory alveolar structures degenerate. Immunofluorescence staining of sections of rat mammary gland with antibodies to 72 KD gelatinase (MMP-2) and stromelysin (MMP-3) revealed increased production of these two proteinases during involution. This increased expression was mostly restricted to myoepithelial cells. Increased expression during involution was also demonstrated by immunoblotting techniques. Gelatin zymography indicated that the predominant metalloproteinase present in involuting rat mammary glands was a 66 KD gelatinase.
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Lund, L. R., S. F. Bjorn, M. D. Sternlicht, B. S. Nielsen, H. Solberg, P. A. Usher, R. Osterby, et al. "Lactational competence and involution of the mouse mammary gland require plasminogen." Development 127, no. 20 (October 15, 2000): 4481–92. http://dx.doi.org/10.1242/dev.127.20.4481.
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Urokinase-type plasminogen activator expression is induced in the mouse mammary gland during development and post-lactational involution. We now show that primiparous plasminogen-deficient (Plg(−/−)) mice have seriously compromised mammary gland development and involution. All mammary glands were underdeveloped and one-quarter of the mice failed to lactate. Although the glands from lactating Plg(−/−) mice were initially smaller, they failed to involute after weaning, and in most cases they failed to support a second litter. Alveolar regression was markedly reduced and a fibrotic stroma accumulated in Plg(−/−) mice. Nevertheless, urokinase and matrix metalloproteinases (MMPs) were upregulated normally in involuting glands of Plg(−/−) mice, and fibrin did not accumulate in the glands. Heterozygous Plg(+/−) mice exhibited haploinsufficiency, with a definite, but less severe mammary phenotype. These data demonstrate a critical, dose-dependent requirement for Plg in lactational differentiation and mammary gland remodeling during involution.
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Talhouk, R. S., M. J. Bissell, and Z. Werb. "Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution." Journal of Cell Biology 118, no. 5 (September 1, 1992): 1271–82. http://dx.doi.org/10.1083/jcb.118.5.1271.
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Extracellular matrix (ECM) plays an important role in the maintenance of mammary epithelial differentiation in culture. We asked whether changes in mouse mammary specific function in vivo correlate with changes in the ECM. We showed, using expression of beta-casein as a marker, that the temporal expression of ECM-degrading proteinases and their inhibitors during lactation and involution are inversely related to functional differentiation. After a lactation period of 9 d, mammary epithelial cells maintained beta-casein expression up to 5 d of involution. Two metalloproteinases, 72-kD gelatinase (and its 62-kD active form), and stromelysin, and a serine proteinase tissue plasminogen activator were detected by day four of involution, and maintained expression until at least day 10. The expression of their inhibitors, the tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1, preceded the onset of ECM-degrading proteinase expression and was detected by day two of involution, and showed a sharp peak of expression centered on days 4-6 of involution. When involution was accelerated by decreasing lactation to 2 d, there was an accelerated loss of beta-casein expression evident by day four and a shift in expression of ECM-remodeling proteinases and inhibitors to a focus at 2-4 d of involution. To further extend the correlation between mammary-specific function and ECM remodeling we initiated involution by sealing just one gland in an otherwise hormonally sufficient lactating animal. Alveoli in the sealed gland contained casein for at least 7 d after sealing, and closely resembled those in a lactating gland. The relative expression of TIMP in the sealed gland increased, whereas the expression of stromelysin was much lower than that of a hormone-depleted involuting gland, indicating that the higher the ratio of TIMP to ECM-degrading proteinases the slower the process of involution. To test directly the functional role of ECM-degrading proteinases in the loss of tissue-specific function we artificially perturbed the ECM-degrading proteinase-inhibitor ratio in a normally involuting gland by maintaining high concentrations of TIMP protein with the use of surgically implanted slow-release pellets. In a concentration-dependent fashion, involuting mammary glands that received TIMP implants maintained high levels of casein and delayed alveolar regression. These data suggest that the balance of ECM-degrading proteinases and their inhibitors regulates the organization of the basement membrane and the tissue-specific function of the mammary gland.(ABSTRACT TRUNCATED AT 400 WORDS)
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Schwertfeger, Kathryn L., Monica M. Richert, and Steven M. Anderson. "Mammary Gland Involution Is Delayed by Activated Akt in Transgenic Mice." Molecular Endocrinology 15, no. 6 (June 1, 2001): 867–81. http://dx.doi.org/10.1210/mend.15.6.0663.
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Abstract Activation of the antiapoptotic protein kinase Akt is induced by a number of growth factors that regulate mammary gland development. Akt is expressed during mammary gland development, and expression decreases at the onset of involution. To address Akt actions in mammary gland development, transgenic mice were generated expressing constitutively active Akt in the mammary gland under the control of the mouse mammary tumor virus (MMTV) promoter. Analysis of mammary glands from these mice reveals a delay in both involution and the onset of apoptosis. Expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor of matrix metalloproteinases (MMPs), is prolonged and increased in the transgenic mice, suggesting that disruption of the MMP:TIMP ratio may contribute to the delayed mammary gland involution observed in the transgenic mice.
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Bernhardt, Sarah M., and Pepper Schedin. "Abstract B011: The anti-cancer effects of vitamin D are blocked postpartum, due to suppression of vitamin D metabolism in the involuting liver." Cancer Prevention Research 15, no. 12_Supplement_1 (December 1, 2022): B011. http://dx.doi.org/10.1158/1940-6215.dcis22-b011.
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Abstract Postpartum mammary gland involution is a physiologic window of increased breast cancer risk. It has been proposed that the poor prognosis associated with postpartum breast cancer is due to the involuting mammary microenvironment promoting progression of indolent lesions to invasive disease. As such, the involuting gland has been implicated as a target for preventive strategies. Vitamin D has anti-cancer properties, and there are data demonstrating that vitamin D supplementation protects against breast cancer progression in mouse models. Moreover, vitamin D deficiency is prevalent in postpartum women, suggesting that vitamin D supplementation during the vitamin D-deficient, at-risk window of involution may be an approach for preventing the progression of indolent lesions. Here, we characterized how vitamin D deficiency and supplementation affect tumor growth in a mouse model of postpartum breast cancer. Vitamin D deficiency and sufficiency were established in BALB/c mice through feeding diets containing low or high levels of vitamin D. Quantification of serum 25(OH)D verified that diets resulted in vitamin D deficiency (25.8±4.3nmol/L;mean±stdev) or sufficiency (66.4±11.7nmol/L) at levels comparable to humans. Murine mammary cancer cells (D2A1, 2×104 cells, 20µL) were injected into mammary fatpads of involuting (2 days post wean), or age-matched nulliparous mice (n=5-12 mice/group), and tumor growth tracked for 4 weeks. Independent of vitamin D status, tumors exposed to the involuting mammary gland grew 1.8-fold larger than tumors exposed to the nulliparous gland (p<0.001); consistent with prior data showing that the microenvironment of the involuting gland is tumor promotional. Interestingly, while vitamin D supplementation of nulliparous mice associated with a 3.4-fold reduction in tumor growth (p=0.03), vitamin D supplementation of involution mice did not reduce tumor growth. Dietary vitamin D is metabolized to its active form in the liver. Our group has previously shown that the liver also undergoes weaning-induced involution. Thus, we tested if involution of the liver impairs metabolism of vitamin D to its active form, potentially contributing to the null effects of vitamin D supplementation in involution mice. We collected serum from mice on vitamin D deficient and supplemented diets across reproductive time points (nulliparous, lactation, involution days 2, 4, 6), and found that vitamin D supplementation during involution was insufficient to restore serum vitamin D to levels of sufficiency. Further, gene expression analysis of livers show that expression of Cyp2r1 and Cyp27a1—genes involved in vitamin D activation—were reduced during involution. Together, these findings suggest that impaired metabolism of vitamin D during involution may reduce the availability of active vitamin D, and contribute to the null effect observed in involution mice. Understanding the mechanisms by which mammary gland involution influences the anti-cancer effects of vitamin D is required to optimize cancer prevention strategies that target this window. Citation Format: Sarah M Bernhardt, Pepper Schedin. The anti-cancer effects of vitamin D are blocked postpartum, due to suppression of vitamin D metabolism in the involuting liver [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B011.
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Jena, Manoj Kumar, and Ashok Kumar Mohanty. "NEW INSIGHTS OF MAMMARY GLAND DURING DIFFERENT STAGES OF DEVELOPMENT." Asian Journal of Pharmaceutical and Clinical Research 10, no. 11 (November 1, 2017): 35. http://dx.doi.org/10.22159/ajpcr.2017.v10i11.20801.
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Mammary gland is a unique organ with its function of milk synthesis, secretion, and involution to prepare the gland for subsequent lactation. The mammary epithelial cells proliferate, differentiate, undergo apoptosis, and tissue remodeling following a cyclic pathway in lactation – involution – lactation cycle, thus fine tuning the molecular events through hormones, and regulatory molecules. Several studies are performed on the mammary gland development, lactogenesis, and involution process in molecular details. The developmental stages of mammary gland are embryonic, pre-pubertal, pubertal, pregnancy, lactation, and involution. Major developmental processes occur after puberty with hormones and growth factors playing crucial role. The two major pathways such as Janus kinases-signal transducer and activator of transcription pathway and PI3K-Akt pathway play a major role in maintaining the lactation. The involution process is a well-orchestrated event involving several signaling molecules and making the gland ready for subsequent lactation. The review focuses on findings with molecular details of different stages of the mammary gland development and signaling pathways involved in lactation–involution cycle. Deep insight into the developmental stages of mammary gland will pave the way to understand mammary gland biology, apoptosis, oncogenesis, and it will help the researchers to use mammary gland as a model for research on various aspects.
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Atabai, Kamran, Rafael Fernandez, Xiaozhu Huang, Iris Ueki, Ahnika Kline, Yong Li, Sepid Sadatmansoori, et al. "Mfge8 Is Critical for Mammary Gland Remodeling during Involution." Molecular Biology of the Cell 16, no. 12 (December 2005): 5528–37. http://dx.doi.org/10.1091/mbc.e05-02-0128.
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Apoptosis is a critical process in normal mammary gland development and the rapid clearance of apoptotic cells prevents tissue injury associated with the release of intracellular antigens from dying cells. Milk fat globule-EGF-factor 8 (Mfge8) is a milk glycoprotein that is abundantly expressed in the mammary gland epithelium and has been shown to facilitate the clearance of apoptotic lymphocytes by splenic macrophages. We report that mice with disruption of Mfge8 had normal mammary gland development until involution. However, abnormal mammary gland remodeling was observed postlactation in Mfge8 mutant mice. During early involution, Mfge8 mutant mice had increased numbers of apoptotic cells within the mammary gland associated with a delay in alveolar collapse and fat cell repopulation. As involution progressed, Mfge8 mutants developed inflammation as assessed by CD45 and CD11b staining of mammary gland tissue sections. With additional pregnancies, Mfge8 mutant mice developed progressive dilatation of the mammary gland ductal network. These data demonstrate that Mfge8 regulates the clearance of apoptotic epithelial cells during mammary gland involution and that the absence of Mfge8 leads to inflammation and abnormal mammary gland remodeling.
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Rivera, Olivia C., Stephen R. Hennigar, and Shannon L. Kelleher. "ZnT2 is critical for lysosome acidification and biogenesis during mammary gland involution." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 315, no. 2 (August 1, 2018): R323—R335. http://dx.doi.org/10.1152/ajpregu.00444.2017.
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Mammary gland involution, a tightly regulated process of tissue remodeling by which a lactating mammary gland reverts to the prepregnant state, is characterized by the most profound example of regulated epithelial cell death in normal tissue. Defects in the execution of involution are associated with lactation failure and breast cancer. Initiation of mammary gland involution requires upregulation of lysosome biogenesis and acidification to activate lysosome-mediated cell death; however, specific mediators of this initial phase of involution are not well described. Zinc transporter 2 [ZnT2 ( SLC30A2)] has been implicated in lysosome biogenesis and lysosome-mediated cell death during involution; however, the direct role of ZnT2 in this process has not been elucidated. Here we showed that ZnT2-null mice had impaired alveolar regression and reduced activation of the involution marker phosphorylated Stat3, indicating insufficient initiation of mammary gland remodeling during involution. Moreover, we found that the loss of ZnT2 inhibited assembly of the proton transporter vacuolar ATPase on lysosomes, thereby decreasing lysosome abundance and size. Studies in cultured mammary epithelial cells revealed that while the involution signal TNFα promoted lysosome biogenesis and acidification, attenuation of ZnT2 impaired the lysosome response to this involution signal, which was not a consequence of cytoplasmic Zn accumulation. Our findings establish ZnT2 as a novel regulator of vacuolar ATPase assembly, driving lysosome biogenesis, acidification, and tissue remodeling during the initiation of mammary gland involution.
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Alexander, Caroline M., Sushma Selvarajan, John Mudgett, and Zena Werb. "Stromelysin-1 Regulates Adipogenesis during Mammary Gland Involution." Journal of Cell Biology 152, no. 4 (February 12, 2001): 693–703. http://dx.doi.org/10.1083/jcb.152.4.693.
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The matrix metalloproteinase MMP-3/stromelysin-1 (Str1) is highly expressed during mammary gland involution induced by weaning. During involution, programmed cell death of the secretory epithelium takes place concomitant with the repopulation of the mammary fat pad with adipocytes. In this study, we have used a genetic approach to determine the role of Str1 during mammary involution. Although Str1 has been shown to induce unscheduled apoptosis when expressed ectopically during late pregnancy (Alexander, C.M., E.W. Howard, M.J. Bissell, and Z. Werb. 1996. J. Cell Biol. 135:1669–1677), we found that during post-lactational involution, mammary glands from transgenic mice that overexpress the tissue inhibitor of metalloproteinases, TIMP-1 (TO), or mice carrying a targeted mutation in Str1 showed accelerated differentiation and hypertrophy of adipocytes, while epithelial apoptosis was unaffected. These data suggest that matrix metalloproteinases (MMPs) do not induce unscheduled epithelial cell death after weaning, but instead alter the stromal microenvironment. We used adipogenic 3T3-L1 cells as a cell culture model to test the function of MMPs during adipocyte differentiation. Fibroblastic 3T3-L1 progenitor cells expressed very low levels of MMPs or TIMPs. The transcription of a number of MMP and TIMP mRNAs [Str1, MT1-MMP, (MMP-14) collagenase-3 (MMP-13), gelatinase A (MMP-2), and TIMP-1, -2 and -3] was induced in committed preadipocytes, but only differentiated adipocytes expressed an activated MMP, gelatinase A. The addition of MMP inhibitors (GM 6001 and TIMP-1) dramatically accelerated the accumulation of lipid during differentiation. We conclude that MMPs, especially Str1, determine the rate of adipocyte differentiation during involutive mammary gland remodeling.
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Feng, Z., A. Marti, B. Jehn, H. J. Altermatt, G. Chicaiza, and R. Jaggi. "Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland." Journal of Cell Biology 131, no. 4 (November 15, 1995): 1095–103. http://dx.doi.org/10.1083/jcb.131.4.1095.
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Milk production during lactation is a consequence of the suckling stimulus and the presence of glucocorticoids, prolactin, and insulin. After weaning the glucocorticoid hormone level drops, secretory mammary epithelial cells die by programmed cell death and the gland is prepared for a new pregnancy. We studied the role of steroid hormones and prolactin on the mammary gland structure, milk protein synthesis, and on programmed cell death. Slow-release plastic pellets containing individual hormones were implanted into a single mammary gland at lactation. At the same time the pups were removed and the consequences of the release of hormones were investigated histologically and biochemically. We found a local inhibition of involution in the vicinity of deoxycorticosterone- and progesterone-release pellets while prolactin-release pellets were ineffective. Dexamethasone, a very stable and potent glucocorticoid hormone analogue, inhibited involution and programmed cell death in all the mammary glands. It led to an accumulation of milk in the glands and was accompanied by an induction of protein kinase A, AP-1 DNA binding activity and elevated c-fos, junB, and junD mRNA levels. Several potential target genes of AP-1 such as stromelysin-1, c-jun, and SGP-2 that are induced during normal involution were strongly inhibited in dexamethasone-treated animals. Our results suggest that the cross-talk between steroid hormone receptors and AP-1 previously described in cells in culture leads to an impairment of AP-1 activity and to an inhibition of involution in the mammary gland implying that programmed cell death in the postlactational mammary gland depends on functional AP-1.
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Hurley, W. L. "Mammary Gland Function During Involution." Journal of Dairy Science 72, no. 6 (June 1989): 1637–46. http://dx.doi.org/10.3168/jds.s0022-0302(89)79276-6.
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Ning, Yun, Bao Hoang, Alwin G. P. Schuller, Tara P. Cominski, Ming-Sing Hsu, Teresa L. Wood, and John E. Pintar. "Delayed Mammary Gland Involution in Mice with Mutation of the Insulin-Like Growth Factor Binding Protein 5 Gene." Endocrinology 148, no. 5 (May 1, 2007): 2138–47. http://dx.doi.org/10.1210/en.2006-0041.
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IGFs (IGF-I and IGF-II) are essential for development, and their bioactivities are tightly regulated by six related IGF-binding proteins (IGFBPs). IGFBP-5 is the most highly conserved binding protein and is expressed in several key developmental lineages as well as in multiple adult tissues including the mammary gland. To explore IGFBP-5 actions in vivo, we produced IGFBP-5 knockout (KO) mice. Whole-body growth, selected organ weights, and body composition were essentially normal in IGFBP-5 KO mice, presumably because of substantial compensation by remaining IGFBP family members. The IGFBP-5 KO mice also exhibited normal mammary gland development and were capable of nursing their pups. We then directly evaluated the proposed role of IGFBP-5 in apoptosis and remodeling of mammary gland during involution. We found that the process of involution after forced weaning was delayed in IGFBP-5 KO mice, with both the appearance of apoptotic cells and the reappearance of adipocytes retarded in mutant mice, compared with controls. We also determined the effects of IGFBP-5 deletion on mammary gland development in pubertal females after ovariectomy and stimulation with estradiol/progesterone. In this paradigm, IGFBP-5 KO mammary glands exhibited enhanced alveolar bud formation consistent with enhanced IGF-I action. These results demonstrate that IGFBP-5, although not essential for normal growth, is required for normal mammary gland involution and can regulate mammary gland morphogenesis in response to hormone stimulation.
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Xuan, Rong, Jianmin Wang, Xiaodong Zhao, Qing Li, Yanyan Wang, Shanfeng Du, Qingling Duan, Yanfei Guo, Zhibin Ji, and Tianle Chao. "Transcriptome Analysis of Goat Mammary Gland Tissue Reveals the Adaptive Strategies and Molecular Mechanisms of Lactation and Involution." International Journal of Molecular Sciences 23, no. 22 (November 20, 2022): 14424. http://dx.doi.org/10.3390/ijms232214424.
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To understand how genes precisely regulate lactation physiological activity and the molecular genetic mechanisms underlying mammary gland involution, this study investigated the transcriptome characteristics of goat mammary gland tissues at the late gestation (LG), early lactation (EL), peak lactation (PL), late lactation (LL), dry period (DP), and involution (IN) stages. A total of 13,083 differentially expressed transcripts were identified by mutual comparison of mammary gland tissues at six developmental stages. Genes related to cell growth, apoptosis, immunity, nutrient transport, synthesis, and metabolism make adaptive transcriptional changes to meet the needs of mammary lactation. Notably, platelet derived growth factor receptor beta (PDGFRB) was screened as a hub gene of the mammary gland developmental network, which is highly expressed during the DP and IN. Overexpression of PDGFRB in vitro could slow down the G1/S phase arrest of goat mammary epithelial cell cycle and promote cell proliferation by regulating the PI3K/Akt signaling pathway. In addition, PDGFRB overexpression can also affect the expression of genes related to apoptosis, matrix metalloproteinase family, and vascular development, which is beneficial to the remodeling of mammary gland tissue during involution. These findings provide new insights into the molecular mechanisms involved in lactation and mammary gland involution.
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CVEK, KATARINA, KRISTINA DAHLBORN, and YVONNE RIDDERSTRÅLE. "Localization of carbonic anhydrase in the goat mammary gland during involution and lactogenesis." Journal of Dairy Research 65, no. 1 (February 1998): 43–54. http://dx.doi.org/10.1017/s0022029997002537.
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The aim of this study was to determine whether carbonic anhydrase (CA) activity in goat mammary capillaries is regulated mainly by local or systemic mechanisms. One gland was dried before the contralateral gland, and after parturition only one gland was milked. Biopsies were taken from the mammary glands of three goats at 14 d intervals during involution and the start of the following lactation. A histochemical method was used to visualize sites of CA activity. To follow the involution process, milk (liquid) samples were taken from both teats each week and analysed for pH and composition. The time course of CA activity disappearance and reappearance in the capillaries was related to changes in milk composition and alveolar area. A dense network of capillaries showing membrane-bound staining for CA was found surrounding the alveoli in the lactating gland. CA activity gradually decreased in the drying gland, although the other gland was being milked. After 8 weeks involution the dried gland had a significantly lower number of stained capillaries than the milked gland. Almost no stained capillaries were found during late pregnancy, when both glands were dried and the tissue growth maximal. During lactation milk pH was 6·6±0·3 and this increased to 7·0±0·1 in the course of involution. In the last trimester of pregnancy the pH returned to its lower value, while the mammary gland was devoid of stained capillaries. Therefore, the capillary CA could not have been directly involved in the pH regulation of milk. The CA activity reappeared in the capillaries directly after delivery, but only in the milked gland. Clearly the regulation of CA activity is influenced more by local than by systemic factors and is associated with the metabolic activity of milk secretion.
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Yi, Yijun, Anne Shepard, Frances Kittrell, Biserka Mulac-Jericevic, Daniel Medina, and Thenaa K. Said. "p19ARFDetermines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development." Molecular Biology of the Cell 15, no. 5 (May 2004): 2302–11. http://dx.doi.org/10.1091/mbc.e03-11-0785.
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This study demonstrated, for the first time, the following events related to p19ARFinvolvement in mammary gland development: 1) Progesterone appears to regulate p19ARFin normal mammary gland during pregnancy. 2) p19ARFexpression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19ARFprotein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19ARFin mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21Cip1and decrease in apoptosis, and 2) p19ARFnull cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21Cip1compared with WT cells. Although, p19ARFis dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19ARFnull mice, the upregulation of p19ARFby progesterone in the WT cells and the weakness of p21Cip1in mammary epithelial cells lacking p19ARFstrongly suggest that the functional role(s) of p19ARFin mammary gland development is critical to sustain normal cell proliferation rate during pregnancy and normal apoptosis in involution possibly through the p53-dependent pathway.
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TATARCZUCH, L., C. PHILIP, and C. S. LEE. "Involution of the sheep mammary gland." Journal of Anatomy 190, no. 3 (April 1997): 405–16. http://dx.doi.org/10.1046/j.1469-7580.1997.19030405.x.
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Li, Meng, Qingzhang Li, and Xuejun Gao. "Expression and function of leptin and its receptor in dairy goat mammary gland." Journal of Dairy Research 77, no. 2 (February 25, 2010): 213–19. http://dx.doi.org/10.1017/s0022029910000063.
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Leptin is an autocrine and paracrine factor which affects the development and function of mammary gland. The purpose of this study was to investigate the presence and regulatory effect of leptin in Chinese Guan Zhong dairy goat mammary gland from the virgin state to involution. The protein expression and localization of leptin and its long form receptor (OB-Rb) were detected by western blot and a confocal laser scanning microscope. Explants were cultured to detect the impacts of leptin on mammary gland, western blot was used to research leptin signal transduction pathway in pregnancy, lactation and involution. Leptin and amounts of OB-Rb protein were high throughout the virgin stage and at the beginning of pregnancy, lower at mid-pregnancy and throughout lactation, then higher at involution. Immunofluorescence performed with the anti-leptin and anti-leptin receptor antibody showed labelling located in adipose, epithelial cells, or extracellular matrix at different stages. The localization of leptin and OB-Rb revealed that leptin induced the expression of OB-Rb specifically and controlled the development and physiological function of the mammary gland by binding to OB-Rb. Leptin stimulated the proliferation and differentiation of ductal epithelial cells in pregnancy by JAK-MAPK signal pathway, enhanced the amount of β-casein in cultured lactating mammary gland by JAK-STAT5 signal pathway, made the mammary duct disappear and induced apoptosis of mammary epithelial cells and mammary gland restitution by JAK-STAT3 signal pathway in involution. Overall, this study demonstrated the importance and complexity of leptin and OB-Rb during mammary gland development and provides a valuable resource for future research in this area.
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Munarini, Nadia, Richard Jäger, Susanne Abderhalden, Gisela Zuercher, Valeria Rohrbach, Saemi Loercher, Brigitte Pfanner-Meyer, Anne-Catherine Andres, and Andrew Ziemiecki. "Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase." Journal of Cell Science 115, no. 1 (January 1, 2002): 25–37. http://dx.doi.org/10.1242/jcs.115.1.25.
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We have previously documented the cell-type-specific and hormone-dependent expression of the EphB4 receptor in the mouse mammary gland. To investigate its role in the biology of the mammary gland, we have established transgenic mice bearing the EphB4 receptor under the control of the MMTV-LTR promoter, which represents the first transgenic mouse model to investigate the effect(s) of unscheduled expression of EphB4 in adult organisms. Transgene expression in the mammary epithelium was induced at puberty, increased during pregnancy, culminated at early lactation and persisted until day three of post-lactational involution. In contrast, expression of the endogenous EphB4 gene is downregulated during pregnancy, is essentially absent during lactation and is re-induced after day three of post-lactational involution. The unscheduled expression of EphB4 led to a delayed development of the mammary epithelium at puberty and during pregnancy. During pregnancy, less lobules were formed, these however exhibited more numerous but smaller alveolar units. Transgenic mammary glands were characterized by a fragile, irregular morphology at lactation; however, sufficient functionality was maintained to nourish the young. Transgenic mammary glands exhibited untimely epithelial apoptotic cell death during pregnancy and abnormal epithelial DNA synthesis at early post-lactational involution, indicating a disturbed response to proliferative/apoptotic signals. Mammary tumours were not observed in the EphB4 transgenic animals; however, in double transgenic animals expressing both EphB4 and the neuT genes, tumour appearance was significantly accelerated and, in contrast to neuT-only animals, metastases were observed in the lung. These results implicate EphB4 in the regulation of tissue architecture, cellular growth response and establishment of the invasive phenotype in the adult mammary gland.
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SOHN, B. Hwa, Hyung-Bae MOON, Tae-Yoon KIM, Han-Sung KANG, Yoon Soo BAE, Kyung-Kwang LEE, and Sun Jung KIM. "Interleukin-10 up-regulates tumour-necrosis-factor-α-related apoptosis-inducing ligand (TRAIL) gene expression in mammary epithelial cells at the involution stage." Biochemical Journal 360, no. 1 (November 8, 2001): 31–38. http://dx.doi.org/10.1042/bj3600031.
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Although interleukin-10 (IL-10) is known to contribute to inflammation and pathogenesis in mammalian organs, little is known about its precise role in the mammary gland. We found that IL-10 levels fluctuated during the mouse mammary cycle, showing little expression at the lactation stage and the highest expression at the involution stage. To reveal the effects of IL-10 on involution, expression profiles of apoptosis-related genes were examined in mice transgenic for IL-10 as well as in IL-10−/− mice. Mild inflammatory lesions by lymphocytes were observed in the mammary glands from four of seven transgenic lines at the lactation stage. It was striking that the expression of tumour-necrosis-factor-α-related apoptosis-inducing ligand (TRAIL) among the apoptosis-related genes was elevated approx. 7-fold in the transgenic mice, whereas others were almost unchanged. Furthermore, TRAIL was down-regulated 4-fold in the IL-10−/− mice at the involution stage. Elevated expression of TRAIL and of death receptor 4 (DR4) protein was identified at the involution stage of normal mammary glands as well as at the lactation stage of the IL-10 transgenic mice. These results indicate that the elevated expression of IL-10 at the involution stage recruits lymphocytes and induces the expression of TRAIL and DR4. These phenomena might partly contribute to apoptosis in the mammary epithelial cells for entering involution.
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SABATAKOS, Georgios, Gareth E. DAVIES, Maria GROSSE, Anthony CRYER, and Dipak P. RAMJI. "Expression of the genes encoding CCAAT-enhancer binding protein isoforms in the mouse mammary gland during lactation and involution." Biochemical Journal 334, no. 1 (August 15, 1998): 205–10. http://dx.doi.org/10.1042/bj3340205.
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Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family have been implicated in the activation of gene expression in the mammary gland during lactation. We have therefore investigated the detailed expression profile of the C/EBP family during lactation and involution of the mouse mammary gland. The expression of C/EBPβ and C/EBPδ mRNA was low during lactation, increased dramatically at the beginning of involution and remained constant thereafter. In contrast, C/EBPα mRNA expression was relatively high during the early stages of lactation, declined to low levels during the late stages of lactation and at the start of involution, and increased again during involution. Electrophoretic mobility-shift assays showed a close correlation between the expression of the C/EBP genes and the functional C/EBP DNA-binding activity and, additionally, demonstrated the participation of heterodimers, formed from among the three proteins, in DNA–protein interactions. The DNA-binding activity of the activator protein 1 (AP1) family of transcription factors was also induced during involution. These results therefore point to potentially important regulatory roles for both the C/EBP and the AP1 family during lactation and involution of the mammary gland.
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Parés, Sílvia, Olivia Cano-Garrido, Alex Bach, Neus Ferrer-Miralles, Antonio Villaverde, Elena Garcia-Fruitós, and Anna Arís. "The Potential of Metalloproteinase-9 Administration to Accelerate Mammary Involution and Boost the Immune System at Dry-Off." Animals 11, no. 12 (November 30, 2021): 3415. http://dx.doi.org/10.3390/ani11123415.
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The dry period is decisive for the milking performance of dairy cows. The promptness of mammary gland involution at dry-off affects not only the productivity in the next lactation, but also the risk of new intra-mammary infections since it is closely related with the activity of the immune system. Matrix metalloproteinase-9 (MMP-9) is an enzyme present in the mammary gland and has an active role during involution by disrupting the extracellular matrix, mediating cell survival and the recruitment of immune cells. The objective of this study was to determine the potential of exogenous administration of a soluble and recombinant version of a truncated MMP-9 (rtMMP-9) to accelerate mammary involution and boost the immune system at dry-off, avoiding the use of antibiotics. Twelve Holstein cows were dried abruptly, and two quarters of each cow received an intra-mammary infusion of either soluble rtMMP-9 or a positive control based on immunostimulant inclusion bodies (IBs). The contralateral quarters were infused with saline solution as negative control. Samples of mammary secretion were collected during the week following dry-off to determine SCC, metalloproteinase activity, bovine serum albumin, lactoferrin, sodium, and potassium concentrations. The soluble form of rtMMP-9 increased endogenous metalloproteinase activity in the mammary gland compared with saline quarters but did not accelerate either the immune response or involution in comparison with control quarters. The results demonstrated that the strategy to increase the mammary gland immunocompetence by recombinant infusion of rtMMP-9 was unsuccessful.
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Gangi, Lisa, Garrison Owens, Robin Humphreys, Lothar Hennighausen, and Edison Liu. "Mammary gland involution studies with cDNA microarrays." Nature Genetics 23, S3 (November 1999): 46. http://dx.doi.org/10.1038/14308.
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Hadsell, Darryl L., Tatiana Alexeenko, Yann Klemintidis, Daniel Torres, and Adrian V. Lee. "Inability of Overexpressed des(1–3)Human Insulin-Like Growth Factor I (IGF-I) to Inhibit Forced Mammary Gland Involution Is Associated with Decreased Expression of IGF Signaling Molecules*." Endocrinology 142, no. 4 (April 1, 2001): 1479–88. http://dx.doi.org/10.1210/endo.142.4.8087.
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Abstract Overexpression of des(1–3) human insulin-like growth factor I (IGF-I) in the mammary glands of transgenic mice (WAP-DES) inhibits apoptosis during natural, but not forced, mammary involution. We hypothesized that this differential response would correlate with the expression of IGF signal transducers. Forced and natural involution were analyzed in nontransgenic and WAP-DES mice beginning on day 16 postpartum. During natural involution, mammary gland wet weight was higher and apoptosis was lower in WAP-DES than in nontransgenic mice. The WAP-DES transgene had no effect on these parameters during forced involution. Mammary tissue concentrations of the transgene protein were 2- to 10-fold higher than those of endogenous IGF-I. Western blot analysis of pooled mammary tissue extracts demonstrated only slightly higher phosphorylation of the IGF signal transducers insulin receptor substrate-1 (IRS-1) and Akt in the WAP-DES than in nontransgenic mice. Dramatic early reductions in phospho-IRS-1, phospho-Akt, IRS-1, IRS-2, and Akt proteins occurred during forced, but not natural, involution. The abundance of the IGF-I receptor and the messenger RNAs for the IGF-I receptors, IRS-1 and -2, were not affected by either genotype or involution. These findings support the conclusions that mammary cells lose their responsiveness to insulin-like signals during forced involution, and that posttranscriptional or posttranslational regulation of IRS-1 and IRS-2 may play a role in this loss.
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Lund, L. R., J. Romer, N. Thomasset, H. Solberg, C. Pyke, M. J. Bissell, K. Dano, and Z. Werb. "Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways." Development 122, no. 1 (January 1, 1996): 181–93. http://dx.doi.org/10.1242/dev.122.1.181.
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Postlactational involution of the mammary gland is characterized by two distinct physiological events: apoptosis of the secretory, epithelial cells undergoing programmed cell death, and proteolytic degradation of the mammary gland basement membrane. We examined the spatial and temporal patterns of apoptotic cells in relation to those of proteinases during involution of the BALB/c mouse mammary gland. Apoptosis was almost absent during lactation but became evident at day 2 of involution, when beta-casein gene expression was still high. Apoptotic cells were then seen at least up to day 8 of involution, when beta-casein gene expression was being extinguished. Expression of sulfated glycoprotein-2 (SGP-2), interleukin-1 beta converting enzyme (ICE) and tissue inhibitor of metalloproteinases-1 was upregulated at day 2, when apoptotic cells were seen initially. Expression of the matrix metalloproteinases gelatinase A and stromelysin-1 and the serine proteinase urokinase-type plasminogen activator, which was low during lactation, was strongly upregulated in parallel starting at day 4 after weaning, coinciding with start of the collapse of the lobulo-alveolar structures and the intensive tissue remodeling in involution. The major sites of mRNA synthesis for these proteinases were fibroblast-like cells in the periductal stroma and stromal cells surrounding the collapsed alveoli, suggesting that the degradative phase of involution is due to a specialized mesenchymal-epithelial interaction. To elucidate the functional role of these proteinases during involution, at the onset of weaning we treated mice systemically with the glucocorticoid hydrocortisone, which is known to inhibit mammary gland involution. Although the initial wave of apoptotic cells appeared in the lumina of the gland, the dramatic regression and tissue remodeling usually evident by day 5 was substantially inhibited by systemic treatment with hydrocortisone. mRNA and protein for gelatinase A, stromelysin-1 and uPA were weakly induced, if at all, in hydrocortisone-treated mice. Furthermore, mRNA for membrane-type matrix metalloproteinase decreased after hydrocortisone treatment and paralleled the almost complete inhibition of activation of latent gelatinase A. Concomitantly, the gland filled with an overabundance of milk. Our data support the hypothesis that there are at least two distinct phases of involution: an initial phase, characterized by induction of the apoptosis-associated genes SGP-2 and ICE and apoptosis of fully differentiated mammary epithelial cells without visible degradation of the extracellular matrix, and a second phase, characterized by extracellular matrix remodeling and altered mesenchymal-epithelial interactions, followed by apoptosis of cells that are losing differentiated functions.
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Clemenceau, Alisson, Caroline Diorio, and Francine Durocher. "Role of Secreted Frizzled-Related Protein 1 in Early Mammary Gland Tumorigenesis and Its Regulation in Breast Microenvironment." Cells 9, no. 1 (January 14, 2020): 208. http://dx.doi.org/10.3390/cells9010208.
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In mice, the lack of secreted frizzled-related protein 1 (SFRP1) is responsible for mammogenesis and hyperplasia, while, in bovines, its overexpression is associated with post-lactational mammary gland involution. Interestingly, there are no reports dealing with the role of SFRP1 in female involution. However, SFRP1 dysregulation is largely associated with human tumorigenesis in the literature. Indeed, the lack of SFRP1 is associated with both tumor development and patient prognosis. Considering the increased risk of breast tumor development associated with incomplete mammary gland involution, it is crucial to demystify the “grey zone” between physiological age-related involution and tumorigenesis. In this review, we explore the functions of SFRP1 involved in the breast involution processes to understand the perturbations driven by the disappearance of SFRP1 in mammary tissue. Moreover, we question the presence of recurrent microcalcifications identified by mammography. In bone metastases from prostate primary tumor, overexpression of SFRP1 results in an osteolytic response of the tumor cells. Hence, we explore the hypothesis of an osteoblastic differentiation of mammary cells induced by the lack of SFRP1 during lobular involution, resulting in a new accumulation of hydroxyapatite crystals in the breast tissue.
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Watson, Christine J. "Post-lactational mammary gland regression: molecular basis and implications for breast cancer." Expert Reviews in Molecular Medicine 8, no. 32 (December 2006): 1–15. http://dx.doi.org/10.1017/s1462399406000196.
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During pregnancy, there is a massive increase in the number of luminal epithelial cells in the breast, which are destined to become the milk factories after birth. These cells are no longer required when the young are weaned, and are removed in a carefully orchestrated event called involution. In this process, the secretory epithelial cells die and are replaced by adipocytes, which redifferentiate as the epithelium is removed. It is essential that the gland is properly remodelled to a pre-pregnant state so that successful lactation can occur following a subsequent pregnancy. Furthermore, failure to remove unnecessary lactational alveoli during weaning could result in inflammation and tissue damage. Recently, it has been shown that components in the fatty stroma in involuting breast can promote metastasis. Thus, it is important to understand the molecular mechanisms that regulate involution, how these can fail, the consequences of the remodelling process, and how this knowledge can inform us about breast cancer. In this review, I discuss the roles of the JAK–STAT, NF-κB and other signalling pathways in the regulation of apoptosis and tissue remodelling during involution.
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Monaghan, P., N. Perusinghe, G. Carlile, and W. H. Evans. "Rapid modulation of gap junction expression in mouse mammary gland during pregnancy, lactation, and involution." Journal of Histochemistry & Cytochemistry 42, no. 7 (July 1994): 931–38. http://dx.doi.org/10.1177/42.7.8014476.
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We investigated the expression of gap junctions in virgin, pregnant, lactating, and involuting mouse mammary gland epithelium with a panel of sequence-specific antibodies to connexins 26, 32, 40 and 43. Indirect immunofluorescence labeling of frozen sections of mammary gland showed that connexin26 was the major connexin in mammary epithelium. Connexins 43, 40, and 32 were not detected. Connexin26 was not detected in the mammary epithelium of virgin mice but was increasingly expressed during pregnancy. At Day 4 of pregnancy, when the mammary gland was composed almost exclusively of ducts, low levels of labeling were detected in the duct epithelium. As pregnancy progressed, the level of labeling with antibodies to connexin26 increased in quantity and intensity. At Day 12, when developing lobules were present, immunolabeling for connexin26 was detected surrounding the developing lumina, which on Day 19 were distended with milk. Labeling of mammary gland reached a maximum on Day 24 (5 days' lactation) but within 24 hr of removal of the litter on Day 28, connexin26 labeling was greatly diminished. No further change in labeling intensity with the antibodies to connexins was detected throughout involution. Double immunofluorescence labeling of 5-day lactating mammary gland with antibodies to connexin26 and anti-keratin 14 or -keratin 19 indicated that the majority of gap junctions detected by this analysis were within the luminal cell population. Western blot analysis of a lactating mammary gland (Day 24) confirmed the absence or low level of expression of connexins 32 and 43, as seen in the immunofluorescence studies, and showed that connexin26 was a dominant antigen expressed in lactating mammary gland epithelium.
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Muraoka, Rebecca S., Anne E. G. Lenferink, Jean Simpson, Dana M. Brantley, L. Renee Roebuck, F. Michael Yakes, and Carlos L. Arteaga. "Cyclin-Dependent Kinase Inhibitor P27Kip1 Is Required for Mouse Mammary Gland Morphogenesis and Function." Journal of Cell Biology 153, no. 5 (May 21, 2001): 917–32. http://dx.doi.org/10.1083/jcb.153.5.917.
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We have studied the role of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 in postnatal mammary gland morphogenesis. Based on its ability to negatively regulate cyclin/Cdk function, loss of p27 may result in unrestrained cellular proliferation. However, recent evidence about the stabilizing effect of p27 on cyclin D1–Cdk4 complexes suggests that p27 deficiency might recapitulate the hypoplastic mammary phenotype of cyclin D1–deficient animals. These hypotheses were investigated in postnatal p27-deficient (p27−/−), hemizygous (p27+/−), or wild-type (p27+/+) mammary glands. Mammary glands from p27+/− mice displayed increased ductal branching and proliferation with delayed postlactational involution. In contrast, p27−/− mammary glands or wild-type mammary fat pads reconstituted with p27−/− epithelium produced the opposite phenotype: hypoplasia, low proliferation, decreased ductal branching, impaired lobuloalveolar differentiation, and inability to lactate. The association of cyclin D1 with Cdk4, the kinase activity of Cdk4 against pRb in vitro, the nuclear localization of cyclin D1, and the stability of cyclin D1 were all severely impaired in p27−/− mammary epithelial cells compared with p27+/+ and p27+/− mammary epithelial cells. Therefore, p27 is required for mammary gland development in a dose-dependent fashion and positively regulates cyclin D–Cdk4 function in the mammary gland.
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Kennedy, S., and H. J. Ball. "Pathology of Experimental Ureaplasma Mastitis in Ewes." Veterinary Pathology 24, no. 4 (July 1987): 302–7. http://dx.doi.org/10.1177/030098588702400403.
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One mammary gland of each of nine primum partum suckling ewes was inoculated with ureaplasma 8 weeks post-partum. Infected glands were swollen, hot, and painful from 16 hours post-infection. Subsequently there was agalactia and reduction in gland size. Histopathologic and ultrastructural examination indicated that the acute phase of the induced mastitis was characterized by necrosis of secretory epithelium with a neutrophil, eosinophil, and macrophage response. Subsequently there was lymphoid infiltration, acinar involution, and fibrosis. This report confirms the pathogenicity of ureaplasma for the ovine mammary gland, and is the first description of the pathologic features of ureaplasmal mastitis in sheep.
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Rieanrakwong, Duangjai, Titaree Laoharatchatathanin, Ryota Terashima, Tomohiro Yonezawa, Shiro Kurusu, Yoshihisa Hasegawa, and Mitsumori Kawaminami. "Prolactin Suppression of Gonadotropin-Releasing Hormone Initiation of Mammary Gland Involution in Female Rats." Endocrinology 157, no. 7 (May 13, 2016): 2750–58. http://dx.doi.org/10.1210/en.2016-1180.
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It has been demonstrated that mammary gland involution after lactation is initiated by accumulation of milk in alveoli after weaning. Here, we report that involution is also dependent on mammary GnRH expression that is suppressed by PRL during lactation. Reduction of plasma prolactin (PRL) by the withdrawal of suckling stimuli increased GnRH and annexin A5 (ANXA5) expression in the mammary tissues after lactation with augmentation of epithelial apoptosis. Intramammary injection of a GnRH antagonist suppressed ANXA5 expression and apoptosis of epithelial cells after forcible weaning at midlactation, whereas local administration of GnRH agonist (GnRHa) caused apoptosis of epithelial cells with ANXA5 augmentation in lactating rats. The latter treatment also decreased mammary weight, milk production, and casein accumulation. Mammary mast cells were strongly immunopositive for GnRH and the number increased in the mammary tissues after weaning. GnRHa was shown to be a chemoattractant for mast cells by mammary local administration of GnRHa and Boyden chamber assay. PRL suppressed the mammary expression of both ANXA5 and GnRH mRNA. It also decreased mast cell numbers in the gland after lactation. These results are the first to demonstrate that GnRH, synthesized locally in the mammary tissues, is required for mammary involution after lactation. GnRH is also suggested to introduce mast cells into the regressing mammary gland and would be in favor of tissue remodeling. The suppression of these processes by PRL is a novel physiological function of PRL.
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RYON, Joel, Lee BENDICKSON, and Marit NILSEN-HAMILTON. "High expression in involuting reproductive tissues of uterocalin/24p3, a lipocalin and acute phase protein." Biochemical Journal 367, no. 1 (October 1, 2002): 271–77. http://dx.doi.org/10.1042/bj20020026.
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During reproduction the mass and number of cells in the uterus and the mammary gland increase rapidly and then diminish more rapidly after their reproductive functions are completed. The diminishment of tissue mass, known as involution, involves an ordered series of events that includes apoptosis of resident cells, neutrophil invasion, the release of degradative enzymes and phagocytosis of cellular debris. Local signals are believed to regulate the progression of involution in each tissue. Here we show that the mammary gland and uterus express high levels of uterocalin, a protein that specifically induces apoptosis in neutrophils and other leucocytes. In the mammary gland, uterocalin expression is induced by weaning. In both tissues, uterocalin is expressed at extremely high levels such that it constitutes an average of 0.2—0.5% of the total extractable protein at its peak. Epithelial cells in the uterus and mammary gland produce uterocalin. In each case, the protein is secreted into the tissue lumen, with mammary-derived uterocalin being found in the milk. The period of highest uterocalin expression invivo is consistent with the hypothesis that one of its physiological roles is to induce apoptosis of infiltrating neutrophils and thereby delay the entry of neutrophils into the tissue. It is proposed that the role of uterocalin during involution is to provide a window of time during which resident cells are protected from the degradative enzymes, free radicals and other secreted products of activated phagocytes to allow these cells to prepare to survive the processes of involution.
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Li, Xiangdong, Anni Wärri, Sari Mäkelä, Tommi Ahonen, Tomi Streng, Risto Santti, and Matti Poutanen. "Mammary Gland Development in Transgenic Male Mice Expressing Human P450 Aromatase." Endocrinology 143, no. 10 (October 1, 2002): 4074–83. http://dx.doi.org/10.1210/en.2002-220181.
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Abstract We recently generated a transgenic mouse strain that expresses the human aromatase gene under the ubiquitin C promoter (AROM+). We have previously shown that in these mice the serum estradiol concentration is highly elevated, whereas the testosterone concentration is decreased. In the present study we examined mammary gland development in AROM+ male mice at different ages and found that the mammary glands of AROM+ males undergo ductal and alveolar development morphologically resembling that of terminally differentiated female mammary glands, expressing mRNA for a milk protein gene (β-casein). The male mammary glands also express multiple hormone receptors typical for female mammary gland: estrogen receptor α and β, progesterone receptor, and PRL receptor. Furthermore, data showed activation of the Stat5 (signal transducer and activator of transcription 5) signaling pathway in the AROM+ male mammary gland. Interestingly, the phenotype observed is in part reversible. Treatment with finrozole, a specific aromatase inhibitor, caused an involution of the differentiated phenotype of the mammary gland, marked by the disappearance of alveolar structures and the majority of the tertiary side branches of the ducts. The present animal model is a valuable tool for better understanding the cellular and molecular mechanisms involved in the development of gynecomastia.
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Ramaswamy, Bhuvaneswari, Neelam Shinde, Morgan Bauer, Maria Cuitino, Saba Mehra, Resham Mawalkar, Mustafa Basree, et al. "Abstract P5-01-08: Mechanistic differences between abrupt and gradual involution of mouse mammary gland." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–01–08—P5–01–08. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-01-08.
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Abstract Objective: Epidemiological studies indicate a direct relation between length of breast feeding and protection against risk of triple negative breast cancer (TNBC), an aggressive subtype. While prolonged breastfeeding allows gradual involution (GI) of the breast, short-term or no breast feeding leads to abrupt involution (AI). We modelled AI and GI of breast in mice, and showed that mice subjected to GI have better protection from tissue remodeling associated injuries in the mammary gland. Our data revealed late development of ductal hyperplasia aided by pro-tumorigenic microenvironment in the AI glands1. Detailed mechanism of mammary gland involution immediately following cessation of lactation has been studied in the past, but only in the AI setting, that is after abrupt removal of pups at the peak of lactation2,3. The goal of this study is to conduct stepwise comparison of the mechanism of GI vs. AI early on to understand the protective effect of GI against breast cancer risk.Methods: Wild-type FVB mice were used in all our studies. Females were mated at 8 weeks of age and uniparous mice were allowed to nurse (6 pups/dam) for 7 days. Females were then assigned randomly to AI or GI cohort. All pups were removed from the AI dams on postnatal day7 (PND7). Three pups each were removed from GI dams on day28 and 31. Mammary glands were harvested intermittently between PND7 and PND35. H&E stained sections were used for histological studies. Unstained FFPE sections were used for immunohistochemistry and TUNEL assay. Total RNA and protein from whole mammary gland was used for qPCR and western blot respectively. Results: GI glands transitioned from fully active lactating to near involuted glands over a period of 8 days (PND17- PND25), while for AI glands it took < 4 days (PND8.5-PND12). The shrinkage and flattening of tall epithelia and loss of acini was gradual in GI glands as opposed to rapid breakdown of acini and adipocyte repopulation in AI gland. Apoptotic cell count peaked on PND11 (5%) in AI vs. PND25 (3%) in GI glands. The pStat3Y705+ cells were highest on PND8.5 (25%) in AI vs. on PND25 (11%) in GI glands. Macrophage infiltration (F4/80+) peaked on PND11 (35%) and remained elevated at ~24% till PND25, while in GI glands increase was gradual from PND17 through PND25 (27%). Expression of key genes identified in AI mice2,3 have markedly different expression pattern in GI mice (Table). While some peaked at a later time point in GI vs. AI coinciding with maximum cell death, expression of some are significantly low or undetectable in GI glands at both RNA and protein level. Conclusions: We show for the first time that kinetics of cell death, adipocyte repopulation, immune cell infiltration and inflammatory state of glands undergoing abrupt vs. gradual involution are markedly different. Several genes known to play a key role during AI are either not expressed or barely detectable in the GI glands at any time point during involution. These data suggests that not only the kinetics, but mechanism of GI and AI are not identical. We conclude that orchestrated cell death in GI protects from drastic lysosomal, and immune cell activities that predisposes mammary glands to higher risk of neoplastic changes.Significance: Epidemiological data highlights the benefits of prolonged breastfeeding in protecting against breast cancer, particularly, TNBC, an aggressive subtype prevalent in the African American women. Our study highlights the mechanism underlying the benefits of gradual involution of breast. GeneFold Change compared to PND7 (GI vs. AI) Peaked on (GI vs. AI)Stat34.0 vs. 5.9PND25 vs. PND8.5Ctsb2.8 vs. 3.4PND25 vs. PND8.5CD143.4 vs. 20PND25 vs. PND8.5Orm11.7 vs. 10PND25 vs. PND12Lrg130 vs. 216PND25 vs. PND12MMP215.8 vs. 27PND25 vs. PND12Chi3L11350 vs. 572, 859PND28 vs. PND11, 28Cebpδnone vs. 4.4None vs. PND8.5CtsLnone vs. 5.7None vs. PND8.5Orm2none vs. 370None vs. PND12Slpinone vs. 92None vs. PND8.5 Citation Format: Bhuvaneswari Ramaswamy, Neelam Shinde, Morgan Bauer, Maria Cuitino, Saba Mehra, Resham Mawalkar, Mustafa Basree, Allen Zhang, Kirti Kaul, Xiaoli Zhang, Ramesh Ganju, Sarmila Majumder. Mechanistic differences between abrupt and gradual involution of mouse mammary gland [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-08.
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Pai, Vaibhav P., Laura L. Hernandez, Malinda A. Stull, and Nelson D. Horseman. "The Type 7 Serotonin Receptor, 5-HT7, Is Essential in the Mammary Gland for Regulation of Mammary Epithelial Structure and Function." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/364746.
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Autocrine-paracrine activity of serotonin (5-hydroxytryptamine, 5-HT) is a crucial homeostatic parameter in mammary gland development during lactation and involution. Published studies suggested that the 5-HT7receptor type was important for mediating several effects of 5-HT in the mammary epithelium. Here, using 5-HT7receptor-null (HT7KO) mice we attempt to understand the role of this receptor in mediating 5-HT actions within the mammary gland. We demonstrate for the first time that HT7KO dams are inefficient at sustaining their pups. Histologically, the HT7KO mammary epithelium shows a significant deviation from the normal secretory epithelium in morphological architecture, reduced secretory vesicles, and numerous multinucleated epithelial cells with atypically displaced nuclei, during lactation. Mammary epithelial cells in HT7KO dams also display an inability to transition from lactation to involution as normally seen by transition from a columnar to a squamous cell configuration, along with alveolar cell apoptosis and cell shedding. Our results show that 5-HT7is required for multiple actions of 5-HT in the mammary glands including core functions that contribute to changes in cell shape and cell turnover, as well as specialized secretory functions. Understanding these actions may provide new interventions to improve lactation performance and treat diseases such as mastitis and breast cancer.
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Watson, Christine J., and Peter A. Kreuzaler. "Remodeling mechanisms of the mammary gland during involution." International Journal of Developmental Biology 55, no. 7-8-9 (2011): 757–62. http://dx.doi.org/10.1387/ijdb.113414cw.
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Sutherland, Kate D., Geoffrey J. Lindeman, and Jane E. Visvader. "The Molecular Culprits Underlying Precocious Mammary Gland Involution." Journal of Mammary Gland Biology and Neoplasia 12, no. 1 (February 24, 2007): 15–23. http://dx.doi.org/10.1007/s10911-007-9034-8.
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Stein, Torsten, Nathan Salomonis, and Barry A. Gusterson. "Mammary Gland Involution as a Multi-step Process." Journal of Mammary Gland Biology and Neoplasia 12, no. 1 (February 16, 2007): 25–35. http://dx.doi.org/10.1007/s10911-007-9035-7.
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Jena, Manoj Kumar, Shalini Jaswal, Sudarshan Kumar, and Ashok Kumar Mohanty. "Molecular mechanism of mammary gland involution: An update." Developmental Biology 445, no. 2 (January 2019): 145–55. http://dx.doi.org/10.1016/j.ydbio.2018.11.002.
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Furth, P. A., U. Bar-Peled, and M. Li. "Apoptosis and mammary gland involution: reviewing the process." Apoptosis 2, no. 1 (1997): 19–24. http://dx.doi.org/10.1023/a:1026454207398.
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Boutinaud, M., JH Shand, MA Park, K. Phillips, J. Beattie, DJ Flint, and GJ Allan. "A quantitative RT-PCR study of the mRNA expression profile of the IGF axis during mammary gland development." Journal of Molecular Endocrinology 33, no. 1 (August 1, 2004): 195–207. http://dx.doi.org/10.1677/jme.0.0330195.
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We have used quantitative RT-PCR to analyse the mRNA expression profile of the major components of the IGF axis in different stages of murine mammary gland development, including late pregnancy, lactation and involution. We have shown that all the genes studied, IGF-I, IGF-II, IGF receptor (IGFR) and IGF-binding protein (IGFBP)-1 to -6, were expressed in every stage, albeit at greatly differing levels and displaying unique expression profiles between developmental stages. IGF-I was always expressed at significantly higher levels than either IGF-II or IGFR. This suggests that IGF-I may be the more important IGF during mammary morphogenesis. Overall, IGFBP-3 demonstrated the highest level of expression of any of the IGFBP genes throughout all the developmental stages studied. However, within developmental stages, by far the highest level of expression of any of the IGFBPs was that of IGFBP-5 at day 2 of involution; this was almost an order of magnitude higher than any of the other IGFBP levels recorded. This corroborated our previous findings that the levels of IGFBP-5 protein are highly elevated in the involuting mammary gland, and demonstrated that this up-regulation of IGFBP-5 operates at the level of transcriptional control or message stability. Comparison of the expression profile for these different genes would strongly suggest that they are likely to have differential functions throughout mammary gland development, and also highlights potential interactions and co-regulation between different members of this axis. In addition, our results have identified some similarities and differences in the expression of IGFBPs between the mouse mammary epithelial cell line, HC11, and the normal mammary gland which are worthy of study, most notably the differential regulation of IGFBP-2 and the site of expression of IGFBP-4 and -6. Overall, this study has demonstrated the importance and complexity of the IGF axis during mammary gland development and provides a valuable resource for future research in this area.
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Plath-Gabler, A., C. Gabler, F. Sinowatz, B. Berisha, and D. Schams. "The expression of the IGF family and GH receptor in the bovine mammary gland." Journal of Endocrinology 168, no. 1 (January 1, 2001): 39–48. http://dx.doi.org/10.1677/joe.0.1680039.
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To study the involvement of the IGFs in mammary development and lactation of the cow, the temporal expressions of IGF-I and -II, its receptor type 1 (IGFR-1), IGF-binding proteins (IGFBPs)-1 to -6 and GH receptor (GHR) mRNA were examined. This was carried out for different stages of mammogenesis, lactogenesis, galactopoiesis and involution in the bovine mammary gland of 26 animals. Furthermore, IGF-I was localised by immunohistochemistry. The highest mRNA concentrations for IGF-I were detected in the mammary tissue of late pregnant heifers (days 255-272) and significantly lower expression was detected during lactogenesis and galactopoiesis. Immunohistochemistry of IGF-I revealed only a weak staining in the epithelium of the ducts during mammogenesis. The epithelium of the alveoli were negative during mammogenesis, lactogenesis and galactopoiesis but displayed distinct IGF-I activity during involution. In the stroma a distinct staining of the cytoplasm of adipocytes and of vascular smooth muscle cells was observed. A certain percentage of fibroblasts (usually 20-30%) were also immunopositive. In contrast, highest expression for IGFR-1 was detected during galactopoiesis and involution. The lowest mRNA concentration for IGFR-1 was found during pregnancy (days 194-213). In general, the expression of IGF-II was not regulated during mammogenesis and lactation, but decreased during involution. The mRNA for the six binding proteins was detected in the bovine mammary gland. The dominant binding proteins were IGFBP-3 and -5. The highest expression of IGFBP-3 was observed during mid-pregnancy and the lowest during late lactation, involution and in non-pregnant heifers. The mRNA for IGFBP-5 increased during late mammogenesis and lactogenesis followed by a decrease thereafter. In general, the mRNA concentrations for IGFBP-2, -4 and -6 were barely detectable during all stages. In contrast, the expression for IGFBP-1 was upregulated in the mammary gland of virgin heifers and increased around the onset of lactation. mRNA for GHR was found during all stages examined without outstanding fluctuations. In conclusion, locally produced IGF-I and -II may mediate mammogenesis. The high mammary IGFR-1 mRNA during lactation suggests a role for peripheral IGF-I in maintenance of lactation. The role of IGFBPs in the mammary gland needs further evaluation.
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Chakraborty, Moumita, and Michal Hershfinkel. "Zinc Signaling in the Mammary Gland: For Better and for Worse." Biomedicines 9, no. 9 (September 12, 2021): 1204. http://dx.doi.org/10.3390/biomedicines9091204.
Full textAbstract:
Zinc (Zn2+) plays an essential role in epithelial physiology. Among its many effects, most prominent is its action to accelerate cell proliferation, thereby modulating wound healing. It also mediates affects in the gastrointestinal system, in the testes, and in secretory organs, including the pancreas, salivary, and prostate glands. On the cellular level, Zn2+ is involved in protein folding, DNA, and RNA synthesis, and in the function of numerous enzymes. In the mammary gland, Zn2+ accumulation in maternal milk is essential for supporting infant growth during the neonatal period. Importantly, Zn2+ signaling also has direct roles in controlling mammary gland development or, alternatively, involution. During breast cancer progression, accumulation or redistribution of Zn2+ occurs in the mammary gland, with aberrant Zn2+ signaling observed in the malignant cells. Here, we review the current understanding of the role of in Zn2+ the mammary gland, and the proteins controlling cellular Zn2+ homeostasis and signaling, including Zn2+ transporters and the Gq-coupled Zn2+ sensing receptor, ZnR/GPR39. Significant advances in our understanding of Zn2+ signaling in the normal mammary gland as well as in the context of breast cancer provides new avenues for identification of specific targets for breast cancer therapy.
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Weng, Ming H., Ting C. Yu, Shuen E. Chen, Ho C. Peh, Wen B. Liu, Ming T. Chen, Hajemi Nagahata, and Chai J. Chang. "Regional accretion of gelatinase B in mammary gland during gradual and acute involution of dairy animals." Journal of Dairy Research 75, no. 2 (May 2008): 202–10. http://dx.doi.org/10.1017/s0022029908003130.
Full textAbstract:
The level of gelatinases in surrounding body fluids of actively remodelling tissue is indicative of basement membrane and extracellular matrix degradation under various physiological and pathological circumstances. To elucidate the association of gelatinase with mammary tissue remodelling during gradual or acute involution, in the first trial, goats milked twice daily (lactation) and goats receiving decreased milking frequency (involution) served to provide a total of 12 milk samples and 11 mammary secretion samples, respectively. In the second trial, 6 cows served to provide samples of dry secretion in 3 consecutive weeks immediately following milk stasis. Gelatin zymography was applied for gelatinase phenotyping and quantification on milk, plasma and the degranulation medium/lysate of milk somatic cells. Results indicated that the most prevalent gelatinase subtype switched from gelatinase A in milk to gelatinase B in involution secretion. Mammary secretion of goats during involution contained marginally higher protein level, significantly lower casein ratio and greater specific capacity of gelatinase B compared with those of milk during lactation. Specific capacities of gelatinases A and B in plasma of goats were similar during lactation and involution, while gelatinase B capacity in degranulation medium/lysates based on unit number of goat somatic cell was significantly higher during involution than during lactation. Milk stasis of cows induced a significant increase in specific capacity of gelatinase B, but not gelatinase A, of dry secretion up to the third week. Results of both trials agree that regional selective accretion of gelatinase B in milk might have played a role in mammary tissue remodelling during involution induced by either decreasing milking frequency or milk stasis. It is suggested that infiltrated polymorphonuclear neutrophils are one of the potential contributors responsible for the accumulation of gelatinase B during involution.
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Plath, A., R. Einspanier, F. Peters, F. Sinowatz, and D. Schams. "Expression of transforming growth factors alpha and beta-1 messenger RNA in the bovine mammary gland during different stages of development and lactation." Journal of Endocrinology 155, no. 3 (December 1, 1997): 501–11. http://dx.doi.org/10.1677/joe.0.1550501.
Full textAbstract:
It is now widely accepted that the mammary gland is under interconnected hormonal and local control. Growth factors are involved in the intercellular signalling of the gland. Our aim was the detection of transforming growth factors alpha (TGF-alpha) and beta 1 (TGF-beta 1) messenger RNA during mammogenesis, lactogenesis, galactopoiesis and involution in the bovine mammary gland (total n = 27). During these stages the RNA was assessed by means of ribonuclease protection assay and reverse transcription-polymerase chain reaction (RT-PCR). To study possible influences of oestrogen, progesterone and prolactin on growth factor expression, mammary RNA was obtained from heifers after induced mammogenesis and lactogenesis, with and without additional prolactin inhibition (total n = 20). Very low levels of TGF-alpha and TGF-beta 1 expression were detected during lactogenesis and galactopoiesis, increasing levels during mammogenesis of primigravid heifers, and highest levels during mammogenesis of virgin heifers and during involution. TGF-alpha expression after induced mammogenesis was greater than after induced lactogenesis or physiological mammogenesis during pregnancy. Furthermore, TGF-alpha mRNA contents increased after prolactin inhibition. TGF-beta 1 expression was almost equal after induced mammogenesis and lactogenesis, but greater than during the physiological mammogenesis and lactogenesis. In conclusion, it can be assumed that growth promoting TGF-alpha and growth inhibiting TGF-beta 1 are co-expressed in the bovine mammary gland. Higher mRNA contents of both factors during mammogenesis and involution may indicate autocrine or paracrine functions for these growth factors during proliferation and reorganisation of the mammary tissue.
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Nguyen, A. V., and J. W. Pollard. "Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution." Development 127, no. 14 (July 15, 2000): 3107–18. http://dx.doi.org/10.1242/dev.127.14.3107.
Full textAbstract:
Involution of the mammary gland following weaning is divided into two distinct phases. Initially, milk stasis results in the induction of local factors that cause apoptosis in the alveolar epithelium. Secondly after a prolonged absence of suckling, the consequent decline in circulating lactogenic hormone concentrations initiates remodeling of the mammary gland to the virgin-like state. We have shown that immediately following weaning TGFbeta3 mRNA and protein is rapidly induced in the mammary epithelium and that this precedes the onset of apoptosis. Unilateral inhibition of suckling and hormonal reconstitution experiments showed that TGFbeta3 induction is regulated by milk stasis and not by the circulating hormonal concentration. Directed expression of TGFbeta3 in the alveolar epithelium of lactating mice using a beta-lactoglobulin promoter mobilized SMAD4 translocation to the nucleus and caused apoptosis of these cells, but not tissue remodeling. Transplantation of neonatal mammary tissue derived from TGFbeta3 null mutant mice into syngenic hosts resulted in a significant inhibition of cell death compared to wild-type mice upon milk stasis. These results provide direct evidence that TGFbeta3 is a local mammary factor induced by milk stasis that causes apoptosis in the mammary gland epithelium during involution.
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Metcalfe, A. D., A. Gilmore, T. Klinowska, J. Oliver, A. J. Valentijn, R. Brown, A. Ross, G. MacGregor, J. A. Hickman, and C. H. Streuli. "Developmental regulation of Bcl-2 family protein expression in the involuting mammary gland." Journal of Cell Science 112, no. 11 (June 1, 1999): 1771–83. http://dx.doi.org/10.1242/jcs.112.11.1771.
Full textAbstract:
Epithelial cells within the mammary gland undergo developmental programmes of proliferation and apoptosis during the pregnancy cycle. After weaning, secretory epithelial cells are removed by apoptosis. To determine whether members of the Bcl-2 gene family could be involved in regulating this process, we have examined whether changes in their expression occur during this developmental apoptotic program in vivo. Bax and Bcl-x were evenly expressed throughout development. However, expression of Bak and Bad was increased during late pregnancy and lactation, and the proteins were present during the time of maximal apoptotic involution. Thereafter, their levels declined. In contrast, Bcl-w was expressed in pregnancy and lactation but was downregulated at the onset of apoptosis. Bcl-2 was not detected in lactating or early involuting mammary gland. Thus, the pro-apoptotic proteins Bax, Bak and Bad, as well as the death-suppressors Bcl-x, Bcl-2 and Bcl-w, are synthesised in mouse mammary gland, and dynamic changes in the expression profiles of these proteins occurs during development. To determine if changes in Bak and Bcl-w expression could regulate mammary apoptosis, their effect on cultured mouse mammary epithelial cells was examined in transient transfection assays. Enforced expression of Bak induced rapid mammary apoptosis, which could be suppressed by coexpression of Bcl-w. In extracts of mammary tissue in vivo, Bak heterodimerized with Bcl-x whereas Bax associated with Bcl-w, but Bak/Bcl-w heterodimers were not detected. Thus, Bak and Bcl-w may regulate cell death through independent pathways. These results support a model in which mammary epithelial cells are primed for apoptosis during the transition from pregnancy to lactation by de novo expression of the death effectors Bak and Bad. It is suggested that these proteins are prevented from triggering apoptosis by anti-apoptotic Bcl-2 family proteins until involution, when the levels of Bcl-w decline. Our study provides evidence that regulated changes in the expression of cell death genes may contribute to the developmental control of mammary apoptosis.
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Zaragozá, R., E. R. García-Trevijano, V. J. Miralles, M. Mata, C. García, R. Carmena, T. Barber, F. V. Pallardó, L. Torres, and J. R. Viña. "Role of GSH in the modulation of NOS-2 expression in the weaned mammary gland." Biochemical Society Transactions 33, no. 6 (October 26, 2005): 1397–98. http://dx.doi.org/10.1042/bst0331397.
Full textAbstract:
GSH delivery to the lactating mammary gland is essential for the maintenance of lactation as its decrease leads to apoptosis and involution of the mammary gland. In fact, it has already been demonstrated that some of the changes in gene expression found in the lactating mammary gland after forced weaning are reproduced in rats treated with buthionine sulphoximine to deplete GSH levels. An oligonucleotide microarray experiment would give us a better knowledge of the mRNA expression patterns during lactation and after weaning and the possible functions of GSH in the modulation of these events.
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Sudhakaran, P. R., M. Ambili, and Susy Philip. "Matrix Metalloproteinase in Mammary Gland Remodeling-Modulation by Glycosaminoglycans." Bioscience Reports 19, no. 5 (October 1, 1999): 485–90. http://dx.doi.org/10.1023/a:1020276609159.
Full textAbstract:
Mammary gland which undergoes proliferation, differentiation and involution in adult life is a useful model system to study the role of extracellular matrix (ECM) in regulating tissue specific functions. The involution that follows weaning results in the suppression of casein gene expression, collapse of alveolar structures and degradation of basement membrane as evidenced by biochemical analysis of matrix components like proteoglycans and collagen. Differential expression of three different MMPs viz. 130 K, 68 K and 60 K with varying specificity to Col IV of basement membrane and Col I of stroma, their selective inhibition by TIMP and proteoglycans and modulation by estrogen highlight the importance of these in the remodeling of the ECM in the mammary gland. The inhibition of these MMPs by glycosaminoglycans, particularly CS and change in the concentration of CS at different stages of mammary gland development suggests the existence of a novel mechanism for the regulation of the activity of MMPs at extracellular sites.
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Bertucci, Paola Y., Ana Quaglino, Andrea G. Pozzi, Edith C. Kordon, and Adali Pecci. "Glucocorticoid-Induced Impairment of Mammary Gland Involution Is Associated with STAT5 and STAT3 Signaling Modulation." Endocrinology 151, no. 12 (September 29, 2010): 5730–40. http://dx.doi.org/10.1210/en.2010-0517.
Full textAbstract:
The mammary epithelium undergoes cyclical periods of cellular proliferation, differentiation, and regression. During lactation, the signal transducer and activator of transcription factor (STAT)-5A and the glucocorticoid receptor (GR) synergize to induce milk protein expression and also act as survival factors. During involution, STAT3 activation mediates epithelial cell apoptosis and mammary gland remodeling. It has been shown that the administration of glucocorticoids at weaning prevents epithelial cell death, probably by extracellular matrix breakdown prevention. Our results show that the synthetic glucocorticoid dexamethasone (DEX) modulates STAT5A and STAT3 signaling and inhibits apoptosis induction in postlactating mouse mammary glands, only when administered within the first 48 h upon cessation of suckling. DEX administration right after weaning delayed STAT5A inactivation and degradation, preserving gene expression of target genes as β-casein (bcas) and prolactin induced protein (pip). Weaning-triggered GR down-regulation is also delayed by the hormone treatment. Moreover, DEX administration delayed STAT3 activation and translocation into epithelial cells nuclei. In particular, DEX treatment impaired the increment in gene expression of signal transducer subunit gp130, normally up-regulated from lactation to involution and responsible for STAT3 activation. Therefore, the data shown herein indicate that glucocorticoids are able to modulate early involution by controlling the strong cross talk that GR, STAT5, and STAT3 pathways maintains in the mammary epithelium.
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Mogus, Joshua Philip. "Exposure to the Endocrine Disruptor, Propylparaben, During Pregnancy and Lactation, Alters Typical Parity-Induced Reorganization of the Mouse Mammary Gland." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A487—A488. http://dx.doi.org/10.1210/jendso/bvab048.997.
Full textAbstract:
Abstract The mammary gland is a hormone sensitive organ that is susceptible to endocrine disrupting chemicals (EDCs) during several vulnerable periods, including pregnancy and lactation. Mammary gland reorganization during pregnancy and lactation is hormone driven and provides long-term protection against breast cancer risk. It is unknown if EDC exposures during these sensitive windows can alter mammary reorganization to either enhance or offset parity-induced protection against breast cancer. Here, we examined effects of propylparaben (PP), a common preservative used in personal care products and foods with estrogen receptor (ER) agonist properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10,000 µg/kg/day PP throughout pregnancy and lactation. These doses were selected for their relevance to human exposures. We also included an unexposed nulliparous female group to evaluate the typical changes associated with parity. Five weeks post-involution (and five weeks after the last PP exposure), mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. We found that PP reduced many of the typical morphological effects of parity on the mammary gland, resulting in intermediate phenotypes for ductal density and total epithelial structures. Notably, we found increased proliferation in PP-treated mammary glands, despite decreased ductal epithelial volume relative to parous controls. Mammary glands from PP-treated females also had alterations in the expression of ERα-mediated genes, including PgR (the gene that encodes progesterone receptor) and Igf1, with expression levels that were intermediate to both nulliparous and parous control mice. Finally, PP reduced the effect of parity on several immune cell types in the mammary gland including B cells, T-cells, and M2 macrophages. These results suggest that PP, at levels relevant to human exposure, can disrupt the normal response to parity in the mouse mammary gland, including persistent alterations to mammary gland structures. Future studies should address whether PP exposures disturb the protective effects of pregnancy on mammary cancer risk.