Progesterone receptor membrane component 1 is required for mammary gland development†

2020 ◽  
Vol 103 (6) ◽  
pp. 1249-1259
Author(s):  
Globinna Kim ◽  
Jong Geol Lee ◽  
Seung-A Cheong ◽  
Jung-Min Yon ◽  
Myeong Sup Lee ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Progesterone Receptor ◽  
Mammary Gland Development ◽  
Target Genes ◽  
Hormone Treatment ◽  
Mammary Glands ◽  
Membrane Component ◽  
Independent Manner ◽  
Receptor Membrane ◽  
Gland Development

Abstract The physiological functions of progesterone (P4) in female reproductive organs including the mammary glands are mediated via the progesterone receptor (PR), but not all P4 functions can be explained by PR-mediated signaling. Progesterone receptor membrane component 1 (PGRMC1), a potential mediator of P4 actions, plays an important role in the ovary and uterus in maintaining female fertility and pregnancy, but its function in mammary glands has not been elucidated. This study investigated the role of PGRMC1 in mouse mammary gland development. Unlike in the uterus, exogenous estrogen (E2) and/or P4 did not alter PGRMC1 expression in the mammary gland, and Pgrmc1-knockout (KO) mice displayed reduced ductal elongation and side branching in response to hormone treatment. During pregnancy, PGRMC1 was expressed within both the luminal and basal epithelium and gradually increased with gestation and decreased rapidly after parturition. Moreover, although lactogenic capacity was normal after parturition, Pgrmc1 KO resulted in defective mammary gland development from puberty until midpregnancy, while the expression of PR and its target genes was not significantly different between wild-type and Pgrmc1-KO mammary gland. These data suggest that PGRMC1 is essential for mammary gland development during puberty and pregnancy in a PR-independent manner.

Expression levels of STAT5A and STAT5B in mammary parenchymal tissue from Upton-Meishan and Large White gilts

2002 ◽  
Vol 82 (4) ◽  
pp. 507-518 ◽  
Author(s):  
M. F. Palin ◽  
D. Beaudry ◽  
C. Roberge ◽  
C. Farmer
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Target Genes ◽  
Mammary Glands ◽  
Mammary Tissue ◽  
Mrna Levels ◽  
Large White ◽  
Parenchymal Tissue ◽  
Tissue Weight ◽  
Gland Development

The implication of STAT5A and STAT5B in mammary gland development and maintenance of lactation is well documented in rodents and humans. However, little is known regarding their roles in mammary gland development during gestation in pigs. We identified and analyzed the complete coding sequences of swine STAT5A and STAT5B and evaluated their mRNA levels in mammary glands of gestating gilts (day 110) in two different breeds, Upton-Meishan and Large White. Sequence analysis revealed a new APASA insertion in the STAT5A amino acid sequence that is in close proximity to residue Tyr 699 and whose phosporylation leads to the activation of target genes’ transcription. STAT5A mRNA levels were higher in Upton-Meishan than in Large White. In both breeds, STAT5B mRNA levels were higher than those of STAT5A , which is contrary to what was found in other mammals. A correlation between circulating IGF-I levels and STAT5B mRNA levels in the mammary gland was noticed in the Upton-Meishan breed only. STAT5B mRNA levels in mammary tissue of Large White gilts were highly correlated with extra-parenchymal tissue weight, parenchymal tissue weight, total parenchymal DNA, RNA and RNA/DNA ratio. In Upton-Meishan gilts, correlations were observed only between extra-parenchymal weight and STAT5A and STAT5B mRNA levels. These results indicate that there are significant differences in mRNA levels of STAT5A and STAT5B in the mammary glands of pregnant gilts when compared to other mammals, and between swine breeds. Key words: Mammary glands, signal transducers, pregnancy, kinases, pig, expression

scholarly journals Target Gene and Function Prediction of Differentially Expressed MicroRNAs in Lactating Mammary Glands of Dairy Goats

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Fei Dong ◽  
Zhi-Bin Ji ◽  
Cun-Xian Chen ◽  
Gui-Zhi Wang ◽  
Jian-Min Wang
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Target Genes ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Mammary Glands ◽  
Differentially Expressed ◽  
Regulatory Function ◽  
Dairy Goats ◽  
Gland Development

MicroRNAs are small noncoding RNAs that can regulate gene expression, and they can be involved in the regulation of mammary gland development. The differential expression of miRNAs during mammary gland development is expected to provide insight into their roles in regulating the homeostasis of mammary gland tissues. To screen out miRNAs that should have important regulatory function in the development of mammary gland from miRNA expression profiles and to predict their function, in this study, the target genes of differentially expressed miRNAs in the lactating mammary glands of Laoshan dairy goats are predicted, and then the functions of these miRNAs are analyzed via bioinformatics. First, we screen the expression patterns of 25 miRNAs that had shown significant differences during the different lactation stages in the mammary gland. Then, these miRNAs are clustered according to their expression patterns. Computational methods were used to obtain 215 target genes for 22 of these miRNAs. Combining gene ontology annotation, Fisher’s exact test, and KEGG analysis with the target prediction for these miRNAs, the regulatory functions of miRNAs belonging to different clusters are predicted.

scholarly journals Progesterone Receptor Isoforms A and B: Temporal and Spatial Differences in Expression during Murine Mammary Gland Development

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3577-3588 ◽  
Author(s):  
Mark D. Aupperlee ◽  
Kyle T. Smith ◽  
Anastasia Kariagina ◽  
Sandra Z. Haslam
Keyword(s):  
Mammary Gland ◽  
Progesterone Receptor ◽  
Cyclin D1 ◽  
Mammary Gland Development ◽  
Minor Role ◽  
Normal Mammary Gland ◽  
Temporal Separation ◽  
Stage Of Development ◽  
Gland Development

Abstract Progesterone is a potent mitogen in the mammary gland. Based on studies using cells and animals engineered to express progesterone receptor (PR) isoforms A or B, PRA and PRB are believed to have different functions. Using an immunohistochemical approach with antibodies specific for PRA only or PRB only, we show that PRA and PRB expression in mammary epithelial cells is temporally and spatially separated during normal mammary gland development in the BALB/c mouse. In the virgin mammary gland when ductal development is active, the only PR protein isoform expressed was PRA. PRA levels were significantly lower during pregnancy, suggesting a minor role at this stage of development. PRB was abundantly expressed only during pregnancy, during alveologenesis. PRA and PRB colocalization occurred in only a small percentage of cells. During pregnancy there was extensive colocalization of PRB with 5-bromo-2′-deoxyuridine (BrdU) and cyclin D1; 95% of BrdU-positive cells and 83% of cyclin D1-positive cells expressed PRB. No colocalization of PRA with either BrdU or cyclin D1 was observed at pregnancy. In the virgin gland, PRA colocalization with BrdU or cyclin D1 was low; only 27% of BrdU-positive cells and 4% of cyclin D1-positive cells expressed PRA. The implication of these findings is that different actions of progesterone are mediated in PRB positive vs. PRA-positive cells in vivo. The spatial and temporal separation of PR isoform expression in mouse mammary gland provides a unique opportunity to determine the specific functions of PRA vs. PRB in vivo.

scholarly journals A Novel LacZ Reporter Mouse Reveals Complex Regulation of the Progesterone Receptor Promoter During Mammary Gland Development

2002 ◽  
Vol 16 (11) ◽  
pp. 2475-2489 ◽  
Author(s):  
Preeti M. Ismail ◽  
Jie Li ◽  
Francesco J. DeMayo ◽  
Bert W. O’Malley ◽  
John P. Lydon
Keyword(s):  
Mammary Gland ◽  
Progesterone Receptor ◽  
Mammary Gland Development ◽  
Lacz Reporter ◽  
Reporter Mouse ◽  
Complex Regulation ◽  
Gland Development

scholarly journals Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands

2003 ◽  
Vol 161 (3) ◽  
pp. 583-592 ◽  
Author(s):  
Rui-An Wang ◽  
Ratna K. Vadlamudi ◽  
Rozita Bagheri-Yarmand ◽  
Iwan Beuvink ◽  
Nancy E. Hynes ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Gland Development ◽  
Mammary Epithelial Cells ◽  
Ectopic Expression ◽  
Functional Differentiation ◽  
Mammary Glands ◽  
Pregnancy And Lactation ◽  
P21 Activated Kinase ◽  
Gland Development

Although growth factors have been shown to influence mammary gland development, the nature of downstream effectors remains elusive. In this study, we show that the expression of p21-activated kinase (Pak)1, a serine/threonine protein kinase, is activated in mammary glands during pregnancy and lactation. By targeting an ectopic expression of a kinase-dead Pak1 mutant under the control of ovine β-lactoglobulin promoter, we found that the mammary glands of female mice expressing kinase-dead Pak1 transgene revealed incomplete lobuloalveolar development and impaired functional differentiation. The expression of whey acidic protein and β-casein and the amount of activated Stat5 in the nuclei of epithelial cells in transgenic mice were drastically reduced. Further analysis of the underlying mechanisms revealed that Pak1 stimulated β-casein promoter activity in normal mouse mammary epithelial cells and also cooperated with Stat5a. Pak1 directly interacted with and phosphorylated Stat5a at Ser 779, and both COOH-terminal deletion containing Ser 779 of Stat5a and the Ser 779 to Ala mutation completely prevented the ability of Pak1 to stimulate β-casein promoter. Mammary glands expressing inactive Pak1 exhibited a reduction of Stat5a Ser 779 phosphorylation. These findings suggest that Pak1 is required for alveolar morphogenesis and lactation function, and thus, identify novel functions of Pak1 in the mammary gland development.

scholarly journals Signal Transducer and Activator of Transcription 5a Mediates Mammary Ductal Branching and Proliferation in the Nulliparous Mouse

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2876-2885 ◽  
Author(s):  
Sarah J. Santos ◽  
Sandra Z. Haslam ◽  
Susan E. Conrad
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Gland Development ◽  
Kinase Inhibitor ◽  
Mammary Epithelial Cells ◽  
Nuclear Factor Κb ◽  
Mammary Glands ◽  
Mammary Epithelial ◽  
Signal Transducer ◽  
Gland Development

Signal transducer and activator of transcription (Stat)5a is a critical regulator of mammary gland development. Previous studies have focused on Stat5a’s role in the late pregnant and lactating gland, and although active Stat5a is detectable in mammary epithelial cells in virgin mice, little is known about its role during early mammary gland development. In this report, we compare mammary gland morphology in pubertal and adult nulliparous wild-type and Stat5a−/− mice. The Stat5a-null mammary glands exhibited defects in secondary and side branching, providing evidence that Stat5a regulates these processes. In addition, Stat5a−/− mammary glands displayed an attenuated proliferative response to pregnancy levels of estrogen plus progesterone (E+P), suggesting that it plays an important role in early pregnancy. Finally, we examined one potential mediator of Stat5a’s effects, receptor activator of nuclear factor-κB ligand (RANKL). Stat5a−/− mammary glands were defective in inducing RANKL in response to E+P treatment. In addition, regulation of several reported RANKL targets, including inhibitor of DNA binding 2 (Id2), cyclin D1, and the cyclin-dependent kinase inhibitor p21Waf1/Cip1, was altered in Stat5a−/− mammary cells, suggesting that one or more of these proteins mediate the effects of Stat5a in E+P-treated mammary epithelial cells.

scholarly journals Chromosomal mapping and quantitative analysis of estrogen-related receptor alpha-1, estrogen receptors alpha and beta and progesterone receptor in the bovine mammary gland

2005 ◽  
Vol 185 (3) ◽  
pp. 593-603 ◽  
Author(s):  
E E Connor ◽  
D L Wood ◽  
T S Sonstegard ◽  
A F da Mota ◽  
G L Bennett ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Progesterone Receptor ◽  
Estrogen Receptors ◽  
Mammary Gland Development ◽  
Chromosomal Mapping ◽  
Mammary Tissue ◽  
Bovine Mammary Gland ◽  
Receptor Alpha ◽  
Gland Development ◽  
Estrogen Related Receptor

Steroid receptors are key transcriptional regulators of mammary growth, development and lactation. Expression of estrogen receptors alpha (ERα) and beta (ERβ), progesterone receptor (PR), and estrogen-related receptor alpha-1 (ERRβ) have been evaluated in bovine mammary gland. The ERRα is an orphan receptor that, in other species and tissues, appears to function in the regulation of estrogen-response genes including lactoferrin and medium chain acyl-CoA dehydrogenase and in mitochondrial biogenesis. Expression of ERα, ERβ, PR and ERRα was characterized in mammary tissue obtained from multiple stages of bovine mammary gland development using quantitative real-time RT-PCR. Expression was evaluated in prepubertal heifers, primigravid cows, lactating non-pregnant cows, lactating pregnant cows and non-lactating pregnant cows (n=4 to 9 animals/stage). In addition, ERα, ERβ, PR and ERRα were mapped to chromosomes 9, 10, 15 and 29 respectively, by linkage and radiation hybrid mapping. Results indicated that expression of ERα, PR and ERRα was largely coordinately regulated and they were present in significant quantity during all physiological stages evaluated. In contrast, ERβ transcripts were present at a very low concentration during all stages. Furthermore, no ERβ protein could be detected in bovine mammary tissue by immunohistochemistry. The ERα and PR proteins were detected during all physiological states, including lactation. Our results demonstrate the presence of ERα, PR and ERRα during all physiological stages, and suggest a functional role for ERRα and a relative lack of a role for ERβ in bovine mammary gland development and lactation.

scholarly journals Abnormal Mammary Gland Development and Growth Retardation in Female Mice and MCF7 Breast Cancer Cells Lacking Androgen Receptor

2003 ◽  
Vol 198 (12) ◽  
pp. 1899-1908 ◽  
Author(s):  
Shuyuan Yeh ◽  
Yueh-Chiang Hu ◽  
Peng-Hui Wang ◽  
Chao Xie ◽  
Qingquan Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Androgen Receptor ◽  
Growth Factor ◽  
Growth Retardation ◽  
Breast Cancer Cells ◽  
Mammary Gland Development ◽  
Mammary Glands ◽  
Factor I ◽  
Gland Development

Phenotype analysis of female mice lacking androgen receptor (AR) deficient (AR−/−) indicates that the development of mammary glands is retarded with reduced ductal branching in the prepubertal stages, and fewer Cap cells in the terminal end buds, as well as decreased lobuloalveolar development in adult females, and fewer milk-producing alveoli in the lactating glands. The defective development of AR−/− mammary glands involves the defects of insulin-like growth factor I–insulin-like growth factor I receptor and mitogen-activated protein kinase (MAPK) signals as well as estrogen receptor (ER) activity. Similar growth retardation and defects in growth factor–mediated Ras/Raf/MAPK cascade and ER signaling are also found in AR−/− MCF7 breast cancer cells. The restoration assays show that AR NH2-terminal/DNA-binding domain, but not the ligand-binding domain, is essential for normal MAPK function in MCF7 cells, and an AR mutant (R608K), found in male breast cancer, is associated with the excessive activation of MAPK. Together, our data provide the first in vivo evidence showing that AR-mediated MAPK and ER activation may play important roles for mammary gland development and MCF7 breast cancer cell proliferation.

In Utero and Lactational Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants Induces a Premature Development of the Mammary Glands

2020 ◽  
Author(s):  
Rita-Josiane Gouesse ◽  
Elham Dianati ◽  
Alec McDermott ◽  
Michael G Wade ◽  
Barbara Hales ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Flame Retardants ◽  
Mammary Gland Development ◽  
Thyroid Hormone Receptor ◽  
Mammary Glands ◽  
Brominated Flame Retardants ◽  
In Utero ◽  
Proliferation Index ◽  
Lactational Exposure ◽  
Gland Development

Abstract In utero and prepubertal development of the mammary glands occurs minimally in a hormone independent manner until puberty where maturation of the hypothalamic-pituitary-gonadal axis drives an extensive remodeling. Nevertheless, because the immature glands contain functional hormone receptors, they are especially vulnerable to the effects of endocrine disruptors, such as brominated flame retardants (BFRs). BFRs are widespread chemicals added to household objects to reduce their flammability, and to which humans are ubiquitously exposed. We previously reported that in utero and lactational exposure to BFRs resulted in an impaired mammary gland development in peripubertal animals. Here, we assessed whether BFR-induced disruption of mammary gland development could manifest earlier in life. Dams were exposed prior to mating until pups’ weaning to a BFR mixture (0, 0.06, 20, or 60 mg/kg/day) formulated according to levels found in house dust. The mammary glands of female offspring were collected at weaning. Histo-morphological analyses showed that exposure to 0.06 mg/kg/day accelerates global epithelial development as demonstrated by a significant increase in total epithelial surface area, associated with a tendency to increase of the ductal area and thickness, and of lumen area. Significant increases of the Ki67 cell proliferation index and of the early apoptotic marker cleaved caspase-9 were also observed, as well as an upward trend in the number of thyroid hormone receptor α1 positive cells. These molecular, histologic, and morphometric changes are suggestive of accelerated pubertal development. Thus, our results suggest that exposure to an environmentally relevant mixture of BFRs induces precocious development of the mammary gland.

scholarly journals Gestational and Lactational Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants Downregulates Junctional Proteins, Thyroid Hormone Receptor α1 Expression, and the Proliferation-Apoptosis Balance in Mammary Glands Post Puberty

2019 ◽  
Vol 171 (1) ◽  
pp. 13-31 ◽  
Author(s):  
Rita-Josiane Gouesse ◽  
Mélanie Lavoie ◽  
Elham Dianati ◽  
Mike G Wade ◽  
Barbara F Hales ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Flame Retardants ◽  
Mammary Gland Development ◽  
Thyroid Hormone Receptor ◽  
Mammary Glands ◽  
Lactational Exposure ◽  
Junctional Proteins ◽  
Gland Development

Abstract Mammary gland development requires hormonal regulation during puberty, pregnancy, and lactation. Brominated flame retardants (BFRs) are endocrine disruptors; they are added to consumer products to satisfy flammability standards. Previously, we showed that gestational and lactational exposure to an environmentally relevant mixture of BFRs disrupts proteins of the adherens junctions in rat dam mammary glands at weaning. Here, we hypothesize that perinatal exposure to the same BFR mixture also disrupts junctional proteins and signaling pathways controlling mammary gland development in pups. Dams were exposed through diet to a BFR mixture based on the substances in house dust; doses of the mixture used were 0, 0.06, 20, or 60 mg/kg/day. Dams were exposed continuously beginning prior to mating until pups’ weaning; female offspring were euthanized on postnatal day (PND) 21, 46, and 208. The lowest dose of BFRs significantly downregulated adherens junction proteins, E-cadherin, and β-catenin, and the gap junction protein p-Cx43, as well as thyroid hormone receptor alpha 1 protein at PND 46. No effects were observed on estrogen or progesterone receptors. The low dose also resulted in a decrease in cleaved caspase-3, a downward trend in PARP levels, proteins involved in apoptosis, and an upward trend in proliferating cell nuclear antigen, a marker of proliferation. No effects were observed on ductal elongation or on the numbers of terminal end buds. Together, our results indicate that gestational and lactational exposure to an environmentally relevant mixture of BFRs disrupts cell-cell interactions, thyroid hormone homeostasis and the proliferation-apoptosis balance at PND 46, a critical stage for mammary gland development.

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