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Abstract
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.
Highlights
The mitogenic activity of estrogen is well established, but an under-studied ovarian steroid hormone, progesterone, is emerging as a primary mitogen in the breast, contributing significantly to genetic programming required for mammary stem cell self-renewal, mammary gland development, proliferation, and hyperplasia [1]
They challenge the current clinical diagnostic paradigm in which progesterone receptor (PR) is only used as a marker of ER transcriptional activity, and support a renewed interest in understanding PR as a driver of breast tumor progression and a potentially very useful target for improved breast cancer therapy [1,86]
We have highlighted the concept that gene-expression analyses linked to PR actions suggest different transcriptional programs are activated in response to specific posttranslational modifications and protein-protein interactions
Summary
The mitogenic activity of estrogen is well established, but an under-studied ovarian steroid hormone, progesterone, is emerging as a primary mitogen in the breast, contributing significantly to genetic programming required for mammary stem cell self-renewal, mammary gland development, proliferation, and hyperplasia [1]. Work recently published from our group suggests a complimentary story whereby ER and PR cooperate to regulate a subset of ER-target genes in response to estrogen, but fully independent of exogenously added progestin In this case, PR-B appears to act as a scaffolding molecule for increased recruitment of signaling adaptors and protein kinases that phosphorylate ER within ER/PR-containing transcription complexes [54]. An in silico analysis of a publically available PR whole genome chromatin immunoprecipitation dataset reveals that there is significant enrichment of STAT5 consensus sites within PR-bound chromatin regions, indicating that STAT5 may function as a pioneer factor for phosphorylated PR (perhaps when PR Ser is phosphorylated) These data suggest that CK2-mediated Ser phosphorylation of PR may activate gene expression programs involved in modulating inflammation related to breast cancer development and progression, including mammary stem cell maintenance and self-renewal. These PR-positive mammary stem cells are devoid of ER protein or mRNA expression, further underscoring the need for understanding PR action as independent of ER in this context
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