Impact of progesterone receptor on cell-fate decisions during mammary 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.

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

Biology of Reproduction ◽

10.1093/biolre/ioaa164 ◽

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.

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

Molecular Endocrinology ◽

10.1210/me.2002-0169 ◽

2002 ◽

Vol 16 (11) ◽

pp. 2475-2489 ◽

Cited By ~ 97

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

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

Journal of Endocrinology ◽

10.1677/joe.1.06139 ◽

2005 ◽

Vol 185 (3) ◽

pp. 593-603 ◽

Cited By ~ 31

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.

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C/EBP (CCAAT/Enhancer Binding Protein) Controls Cell Fate Determination during Mammary Gland Development

Molecular Endocrinology ◽

10.1210/me.14.3.359 ◽

2000 ◽

Vol 14 (3) ◽

pp. 359-368 ◽

Cited By ~ 37

Author(s):

T. N. Seagroves

Keyword(s):

Mammary Gland ◽

Cell Fate ◽

Mammary Gland Development ◽

Binding Protein ◽

Cell Fate Determination ◽

Fate Determination ◽

Enhancer Binding Protein ◽

Ccaat Enhancer Binding Protein ◽

Gland Development

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A noncoding RNA is a potential marker of cell fate during mammary gland development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0600745103 ◽

2006 ◽

Vol 103 (15) ◽

pp. 5781-5786 ◽

Cited By ~ 121

Author(s):

M. R. Ginger ◽

A. N. Shore ◽

A. Contreras ◽

M. Rijnkels ◽

J. Miller ◽

...

Keyword(s):

Mammary Gland ◽

Cell Fate ◽

Noncoding Rna ◽

Mammary Gland Development ◽

Potential Marker ◽

Gland Development

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A paracrine role for the epithelial progesterone receptor in mammary gland development

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.9.5076 ◽

1998 ◽

Vol 95 (9) ◽

pp. 5076-5081 ◽

Cited By ~ 255

Author(s):

C. Brisken ◽

S. Park ◽

T. Vass ◽

J. P. Lydon ◽

B. W. O'Malley ◽

...

Keyword(s):

Mammary Gland ◽

Progesterone Receptor ◽

Mammary Gland Development ◽

Gland Development

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Progesterone Receptor Isoforms and Proliferation in the Rat Mammary Gland during Development

Endocrinology ◽

10.1210/en.2006-1493 ◽

2007 ◽

Vol 148 (6) ◽

pp. 2723-2736 ◽

Cited By ~ 38

Author(s):

Anastasia Kariagina ◽

Mark D. Aupperlee ◽

Sandra Z. Haslam

Keyword(s):

Mammary Gland ◽

Progesterone Receptor ◽

Mammary Gland Development ◽

Kinase Inhibitors ◽

Expression Patterns ◽

Significant Proportion ◽

Myoepithelial Cells ◽

Normal Mammary Gland ◽

Rat Mammary Gland ◽

Gland Development

Progesterone (P), acting through progesterone receptor (PR) isoforms A and B, plays an important role in normal mammary gland development and is implicated in the etiology of breast cancer. Because of significant similarities between human and rat mammary gland development and hormonal responsiveness of mammary cancers, we investigated P action in the rat mammary gland. By immunohistochemical methods we determined PRA and PRB expression at puberty, sexual maturity, pregnancy, and lactation and after postlactational involution and their functional roles in the regulation of proliferation. PRA expression was restricted to luminal epithelial cells, whereas PRB was expressed in both luminal and myoepithelial cells, indicating a novel role of PRB in myoepithelial cell regulation. The majority of PRA-positive (PRA+) cells coexpressed PRB. In the pubertal and adult virgin mammary gland, PRA+PRB+ cells also expressed nuclear cyclin D1 but did not contain the proliferation marker bromodeoxyuridine. Based on a lack of phosphorylated retinoblastoma protein expression and the expression patterns of the cyclin-dependent kinase inhibitors p21 and p27 in these cells, we conclude that PRA+PRB+ cells appear to be cell cycle arrested and do not proliferate. PRA+ cells were decreased in the adult gland and during and after pregnancy. The percentage of PRB+ cells was relatively constant throughout development, and in a significant proportion of cells, only PRB was detected. During development, and especially during pregnancy, a high percentage of PRB+ cells were positive for bromodeoxyuridine. From this observation, we conclude that these cells proliferate and that P acting through PRB may directly stimulate proliferation.

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