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Steroid hormones are required for normal breast development and play a key role in breast cancer. The steroid hormone progesterone regulates cell growth in the normal mammary gland and uterus by cell cycle phase-specific actions. Breast cancers are often characterized by increased growth factor signaling pathways and numerous cell cycle alterations, including decreased levels of p27 and increased levels of cyclins D1, D2 and E. Progestins, via the activation of progesterone receptor (PR), activate cyclin dependent kinase 2 (CDK2) and raise levels of cyclins D and E> PR are phosphorylated by CDK2 in vitro and in vivo at multiple sites including serine 400 (Ser400). In addition, breast cancer cell growth is controlled, in part by, cross-talk between steroid hormone and growth factor signaling pathways. The purpose of these studies is to investigate the role that growth factors and cell cycle molecules play on the regulation of PR by phosphorylation of Ser400.
Breast cancers are often characterized by increased growth factor signaling pathways and numerous cell cycle alterations. PR are phosphorylated by CDK2 in vitro and in vivo at multiple sites including serine 400 (Ser400). The purpose of these studies is to investigate the role that growth factors and cell cycle molecules play on the regulation of PR by phosphorylation of Ser400. Treatment of T47D breast cancer cells with mitogens increased the phosphorylation of PR Ser400, as did the synthetic progestin R5020. Progestin dependent phosphorylation of Ser400 was reversed by a CDK2 inhibitor. Overexpression of cyclin E and CDK2 resulted in downregulation of PR protein in the absence of ligand. This effect was blocked by a CDK2 inhibitor. P27 is a cyclin-dependent kinase inhibitory protein. A p27-/-cell line was used to measure the transcriptional activity of PR following transient co-transfection of PR and a progesterone responsive-element Ligand-independent PR transcriptional activity was elevated in p27-/-cells; mutation of PR serine 400 to alanine resulted in loss of PR transcriptional activity. In' addition, cyclin E and CDK2 associated with wt PR in co-immunoprecipitation experiments. Regulation of PR by altered cyclin/CDKs may confer a selective advantage to breast cancer cells.
Growth and development of the mammary gland are controlled by the female hormones estrogen and progesterone. These hormones affect breast cancer growth and are targets for hormonal therapy. For this reason, it is important to understand the role of these hormones in the proliferation of mammary epithelial cells. We have characterized how these hormones may be interacting with the cell cycle machinery. The cell cycle machinery orchestrates the events required for cells to proliferate. It is composed of cyclins and their catalytic partners known as cyclin dependent kinases. We have addressed how estrogen and progesterone affect expression and activities of these cell cycle molecules. We have shown that estrogen can induce cyclin D1 expression and activate cyclin E-cdk2 complexes in breast cancer cells. We have also investigated the relationship between progesterone and cyclin D1 using mice lacking either cyclin D1 or the progesterone receptor. Both strains have a defect in mammary gland development We postulated that cyclin Dl may be regulated by progesterone during pregnancy. However, mammary glands lacking cyclin Dl responded to progesterone like nominal mammary glands. In conclusion, we have studied the role of estrogen and progesterone in regulating the cell cycle of mammary epithelial cells. Understanding the growth regulatory mechanisms affected by these hormones may lead to new ways of breast cancer therapy.
Our studies show that agonist-bound PR-B can stimulate the proliferation of breast cancer cells by functioning in a direct manner to induce transcription of E2F1 and E2F2, key regulators of cell cycle progression. We demonstrate that although the MAPK pathway is important for phosphorylation of RB and release of E2F, its activation is not dependent on PR signaling through Src family kinases. Further, we found that PRMs such as asoprisnil that do not induce classic PR target genes can activate E2F signaling and stimulate proliferation. Future studies will explore this novel mechanism by which PR regulates breast cancer proliferation so that we can better enable development of PRMs that effectively inhibit breast tumor growth.
Progesterone (P4) imparts distinct effects in the breast via its progesterone receptors (PRs) PRA and PRB. Since the gap junction and tumour suppressor protein Connexin 43 (Cx43) is differentially regulated by P4 via PRA/B in human myometrial cells, we sought to delineate the roles of PRA/B on Cx43 in breast cancer cells. We hypothesize that, similar to myometrial cells, the two PRs differentially affect Cx43 expression, trafficking, and gap junction intercellular communication (GJIC) in breast cancer cells. In this project, I have shown that in the luminal A cell line MCF7, PRA promotes Cx43 expression, trafficking (similarly observed in the cell line MFM223), and GJIC whereas PRB inhibits these processes. Conversely, in the basal-like cell line MDA-MB-231, P4 inhibits Cx43 expression, intracellular trafficking, and GJIC through both PRs. These data provide insight as to how PRs differentially regulate the same gene, Cx43, in contrasting in vitro models of breast cancer.