Progesterone Receptor Scaffolding Function in Breast Cancer.

摘要

Progesterone receptors (PR) are critical mediators of mammary gland development and contribute to breast cancer progression. Progestin-induced rapid activation of cytoplasmic protein kinases leads to selective regulation of growth-promoting genes by phospho-PR species. We have shown that phosphorylation of PR Ser81 is ck2- dependent, progestin-regulated and cell cycle-dependent in intact cells. Mutation of the CD domain in PR (mCD PR) abrogates phosphorylation on Ser81, indicating that the CD domain in necessary to facilitate phosphorylation at this site (Ser81). Additionally, we showed that an interaction between PR and MKP3, a regulator of the ERK family, is dependent on the CD domain. Regulation of selected genes by PR-B also required the CD domain for basal and/or progestin-regulated (STAT5A, Wnt1, MKP3) expression/repression. We conclude that the CD domain of PR facilitates protein interactions that are critical to PR-dependent transcription of genes involved in proliferation and mammary stem cell maintenance. Experiments to determine how MKP3 binding mechanistically regulates transcription of these genes, as well as phosphorylation at Ser81 (by ck2) are currently underway. Understanding how mitogenic protein kinases, such as ck2, alter PR phosphorylation and function is critical to fully understanding breast tumor etiology and developing better targeted therapies. Recent clinical data linking the progesterone component of hormone-replacement therapy regimens with the development of breast cancer underscores the importance of understanding how PR works in the context of breast cancer and high kinase environments.