Progesterone and estrogen receptors segregate into different cell subpopulations in the normal human breast

Hilton, Heidi N.; Graham, J. Dinny; Kantimm, Silke; Santucci, Nicole; Cloosterman, D.; Huschtscha, Lily I.; Mote, Patricia A.

doi:10.1016/j.mce.2012.04.010

Cited by 39 publications

(38 citation statements)

References 61 publications

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“…Progesterone induces mammary stem cell expansion (3). Interestingly, Hilton et al (26) showed that the presence of PR-and basal markers-positive bi-potent progenitor cells in normal human breast. In contrast to the luminal epithelial cells, these PR-positive bi-potent progenitor cells are refractory to estrogen.…”

Section: Discussionmentioning

confidence: 99%

Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

Wang

Liu

Hsu

et al. 2013

Journal of Biological Chemistry

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Background: Stabilization of progesterone receptors contributes to mammary tumorigenesis in Brca1-deficient mice. Results: Deficiency in phosphorylation on serine 390 of progesterone receptor A by GSK-3␤ enhances the receptor stability. Conclusion: Stabilization of progesterone receptor A is mediated by GSK-3␤ kinase in the Brca1-deficient mammary gland. Significance: This finding provides a novel insight of how tumor suppression of Brca1 is mediated by PR-A.

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Section: Discussionmentioning

confidence: 99%

Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

Wang

Liu

Hsu

et al. 2013

Journal of Biological Chemistry

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“…The authors then demonstrated that this subset was enriched for bipotent progenitor activity, as determined by colony forming cell assays, and contained high PR transcript levels [28]. This was later supported in the model of human breast epithelial cells embedded in 3D culture, with the detection of high levels of PR transcripts in both the bipotent progenitorenriched compartment, as well as in the basal-enriched EpCAM+CD49f+ cell sub-fraction of normal human breast [89]. The EpCAM+CD49f+ fraction was also shown to express PR protein, as confirmed by flow cytometry [89].…”

Section: Pr Expression In Stem/progenitor Cellsmentioning

confidence: 83%

“…Co-expression of PR and CK14 was observed in both uncultured primary human breast epithelial cells, as well as in breast epithelial cells grown in 3D culture [89]. Moreover, expression of PR in a subset of CK14+ cells was observed only in sorted cells which had been enriched for those with bipotent progenitor characteristics, while there was complete segregation of PR and CK14 in the cell fraction which contained differentiated luminal and myoepithelial cells [89].…”

Section: Pr Expression In Stem/progenitor Cellsmentioning

confidence: 96%

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Impact of Progesterone on Stem/Progenitor Cells in the Human Breast

Hilton

2015

J Mammary Gland Biol Neoplasia

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The epithelium of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal cells surrounded by a contractile basal cell layer. The co-ordinated development of stem/progenitor cells into these luminal and basal cells is fundamentally important for breast morphogenesis. The ovarian steroid hormone, progesterone, is critical in driving proliferation and normal breast development, yet progesterone analogues have also been shown to be a major driver of breast cancer risk. Studies in recent years have revealed an important role for progesterone in stimulating the mammary stem cell compartment in the mouse mammary gland, and growing evidence supports the notion that progesterone also stimulates progenitor cells in both the normal human breast and in breast cancer cells. As changes in cell type composition are one of the hallmark features of breast cancer progression, these observations have critical implications in discerning the mechanisms of how progesterone increases breast cancer risk. This review summarises recent work regarding the impact of progesterone action on the stem/progenitor cell compartment of the human breast.

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“…This observation is similar to what has been published for PR regulation of WNTs [8], highlighting an emerging role for co-ordinate STAT5/PR regulation of select subsets of PR-target genes related to proliferation and stem cell selfrenewal (see above). Moreover, a PR-positive subpopulation of mammary gland progenitor cells has been recently discovered [61], challenging the current dogma that mammary gland precursors are strictly SR-negative. These exciting findings suggest that this long-lived population of cells, one that is exquisitely sensitive to mutagenic events, can expand in response to progesterone in both a paracrine and autocrine fashion [36].…”

Section: Progesterone Receptor Clinical Significance In Breast Cancermentioning

confidence: 97%

FOXA1 Promotes Tumor Cell Proliferation through AR Involving the Notch Pathway in Endometrial Cancer

2014

Cancer Cell Signaling

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The ovarian steroid hormone, progesterone, and its nuclear receptor, the progesterone receptor, are implicated in the progression of breast cancer. Clinical trial data on the effects of hormone replacement therapy underscore the importance of understanding how progestins influence breast cancer growth. The progesterone receptor regulation of distinct target genes is mediated by complex interactions between the progesterone receptor and other regulatory factors that determine the context-dependent transcriptional action of the progesterone receptor. These interactions often lead to post-translational modifications to the progesterone receptor that can dramatically alter receptor function, both in the normal mammary gland and in breast cancer. This review highlights the molecular components that regulate progesterone receptor transcriptional action and describes how a better understanding of the complex interactions between the progesterone receptor and other regulatory factors may be critical to enhancing the clinical efficacy of anti-progestins for use in the treatment of breast cancer.

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Progesterone and estrogen receptors segregate into different cell subpopulations in the normal human breast

Cited by 39 publications

References 61 publications

Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

Impact of Progesterone on Stem/Progenitor Cells in the Human Breast

FOXA1 Promotes Tumor Cell Proliferation through AR Involving the Notch Pathway in Endometrial Cancer

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