Progesterone is an ovarian steroid hormone essential for breast development. The progesterone receptor (PR) exists primarily in two co-expressed isoforms, PR-A and PR-B. Studies from knockout-mice have shown that PR-B is required for proliferative signaling during mammary gland alveologenesis. In contrast, PR-A is required for uterine development, where progesterone inhibits proliferation. Very little is understood regarding regulation of PR tissue- and isoform-specific transcription. How are isoform-specific mitogenic (PR-B in the breast) and inhibitory/differentiative (PR-A in the uterus) effects achieved? PR-A and PR-B are most often co-expressed in the same tissues, and cells that express only a single PR isoform are rare, except in breast cancer where the normal 1:1 ratio is frequently altered. Selective PR isoform inhibition (blocking pro-proliferative effects of PR-B while preserving the protective or anti-proliferative effects of PR-A) would represent significant progress in breast cancer prevention and/or treatment. PR is highly post-translationally modified. Phosphorylation, primarily on PR-B N-terminal serine residues, significantly alters receptor stability, localization, transcriptional activity and promoter selectvity. Our preliminary data suggest that the basis for PR-B-specific proliferative actions in breast cancer cells involves ck2-dependent selective phosphorylation of PR-B Ser81 via a unique protein interaction domain, the common docking (CD) domain, found exclusively in PR-B but not PR-A. Phosphorylation of PR-B Ser81 regulates a highly specific subset of proliferative and pro-survival genes, including selected PR-regulated genes known to modulate the mammary stem cell compartment, such as Wnt1 and STAT5A. Additionally, our data suggest that STAT5A may serve as a "pioneer factor", an early genomic binding partner that recruits/directs phospho-Ser81-PR-B-specific gene regulation. The goal of this research proposal is to determine how proteins that interact with PR-B via the CD domain regulate direct phosphorylation of PR-B on Ser81, thereby dictating PR-B isoform-specific transcriptional events at genes important for breast cancer cell proliferation, pro-survival, and expansion of the stem cell compartment. Hypothesis: PR and STAT5 co-regulate a specific subset of phospho-PR-B target genes (through CD domain- dependent recruitment of MKP3 and ck2, followed by ck2-mediated phosphorylation of PR-B Ser81) that regulate breast cancer cell proliferation and pro-survival, in part via modulation of the mammary stem cell compartment;selected genes are regulated by phospho-PR-B in the absence of ligand. ck2-dependent activation of PR-B may accelerate mammary tumor development and/or drive early breast cancer progression.
The goal of this research proposal is to determine how proteins that interact with the progesterone receptor (PR) regulate its direct phosphorylation, thereby dictating PR isoform-specific transcriptional events at genes important for breast cancer cell proliferation, pro-survival, and expansion of the stem cell compartment. Understanding how PR isoform-specific regulation is achieved may allow us to modulate/inhibit the proliferative actions of PR in the breast, while preserving protective anti-proliferative activities in other tissues. These studies could open the way to new treatments that may prevent or reverse the development of early cancerous steroid receptor positive breast lesions and/or provide novel PR-based additions to the current repertoire of largely estrogen receptor-based endocrine therapies.
|Hagan, Christy R; Knutson, Todd P; Lange, Carol A (2013) A Common Docking Domain in Progesterone Receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells. Nucleic Acids Res 41:8926-42|