Interestingly, patients whose tumor gene sig nature resembled that of T47D cells expressing KR R5020 trended toward poorer outcome. To include the contribution of LI PR target genes, learn more we combined patients whose tumors expressed both KR metagenes. These patients experienced significantly reduced distant metastasis free survival relative to those whose tumors did not express either of the two KR metagenes. With respect to node and grade, there was no apparent association with expression of the metagenes. These data suggest that PR dependent transcription, and in particular, the actions of the deSUMOylated receptor, contribute to rapid tumor pro gression and poor outcome in a subset of breast cancer patients. Discussion In this study, we performed gene expression profiling to understand better how PR SUMO modification impacts transcriptional activity and promoter selection.

Using newly engineered breast cancer cell line models, we identified a PR driven gene signature that is present in human tumors and associated with decreased patient survival. Previously, we showed that PR phosphorylation at Ser294 antagonizes PR SUMOy lation at Lys388. Our novel data suggest that breast cancer cells may utilize this Inhibitors,Modulators,Libraries mechanism to shift PR tran scriptional action toward target genes that drive cell proliferation Inhibitors,Modulators,Libraries and pro survival pathways. Using bioinformatics Inhibitors,Modulators,Libraries to analyze global gene expres sion levels, we identified dramatic differences in transcriptional responses between WT and deSUMOylated PRs that were further characterized by ChIP analysis as alterations in promoter enhancer selectivity.

Additionally, treatment of unmodified breast cancer cells with EGF further implicated PR Ser294 phosphorylation in transcriptional derepression of selected Inhibitors,Modulators,Libraries PR target genes. Notably, genes spe cifically upregulated by SUMO Inhibitors,Modulators,Libraries deficient PR are significantly associated with genes that are highly expressed in ERBB2 Alisertib structure positive human breast tumors and cell lines, our studies support a mechanistic link between phosphorylated PR B specific transcriptional action and expres sion of a subset of ERBB2 associated genes. Collectively, our data provide a strong rationale for further study into mechanisms of phospho PR depen dent regulation of transcription and the potential contri bution of this activity to early or rapid breast cancer progression towards endocrine resistance. Gene expression analysis identifies SUMOylation sensitive PR target genes We previously reported that PR SUMOylation is tran scriptionally repressive at a limited number of endogen ous gene loci, including HBEGF, IRS1, and STC1, all three gene products are known to contribute to breast cancer cell proliferation.