摘要：
Progesterone receptors (PR) are emerging as important breast cancer drivers. Elevated mitogen activated protein kinase (MAPK) and cyclin dependent kinase 2 (CDK2) signaling is common in breast cancer and these kinases drive direct PR-B, but not PR-A, Ser294 phosphorylation. Post-translational modifications, including phosphorylation and SUMOylation, dramatically impact PR transcriptional activity. Phospho-Ser294 PRs are less SUMOylated on Lys388 (i.e. a repressive modification). Thus, active mitogenic kinase signaling provides a mechanism for PR derepression (i.e. transcriptional activation) during breast cancer progression. A broad range of PR protein expression is observed clinically; PR-negative tumors are generally more aggressive. However, clinical (IHC) assays do not measure phospho-PRs, which turnover rapidly and may appear undetectable, confounding the true level of activated PR within tumors. A PR gene signature would provide a valuable marker of PR contribution to breast cancer progression. Global gene expression patterns were measured in T47D and MCF-7 breast cancer cells expressing either wild type or K388R (SUMOylation-deficient) PRs and subjected to pathway analysis. Target genes sensitive to changes in PR SUMOylation included those required for proliferative and pro-survival signaling. DeSUMOylated K388R receptors were preferentially recruited to enhancer regions of derepressed genes. SUMO-deficient (i.e. phospho-Ser294) PR gene signatures were significantly associated with human epidermal growth factor 2 (ERBB2)-positive luminal breast tumors and predictive of early metastasis and shortened survival. Furthermore, treatment with antiprogestin or MEK inhibitors abrogated expression of SUMO-sensitive PR target-genes and inhibited progestin-driven proliferation in BT-474 (estrogen receptor (ER)+/PR+/ERBB2+) breast cancer cells. Similarly, treatment of T47D cells expressing deSUMOylated PR with ERBB2 inhibitors blocked progestin-dependent growth. Potential mechanisms of differential promoter selection were investigated. Notably, genes preferentially up-regulated by SUMO-deficient PR contain RUNX binding motifs located near their transcriptional start sites. Herein, we demonstrated that RUNX2 directly interacts with PR. Further, RUNX2 knockdown in breast cancer cells reduced SUMO-deficient PR dependent gene expression. Our studies suggest that deSUMOylated PR cooperates with RUNX2 to mediate promoter selective gene expression. We conclude that reversible PR SUMOylation/deSUMOylation profoundly alters PR target gene selection in breast cancer cells, in part via regulation of PR interactions with gene-specific co-factors, such as RUNX2. Patients whose ER+/PR+ tumors are driven by hyperactive phospho-PRs may benefit from endocrine (antiestrogen) therapies that also contain an antiprogestin.
展开
扫一扫
被折叠的 条评论
为什么被折叠?
到【灌水乐园】发言
