PLX283790

GSE80358: PR isoform-specific ER and PR chromatin binding and gene expression observed in-vitro in breast cancer cells.

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR dictates distinct ER and PR chromatin binding and differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Genomic analyses of the two PR isoforms, PRA and PRB, indicate that these isoforms bind distinct genomic sites and interact with different sets of co-regulators to differentially modulate gene expression as well as pro- or anti-tumorigenic phenotypes. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Of note, the two isoforms reprogrammed estrogen activity to be either pro or anti-tumorigenic. In concordance to the in-vitro observations, differential gene expression was observed in PRA and PRB-rich patient tumors and importantly, PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. This differential of better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher anti-tumor activity of combination therapies of tamoxifen with PR antagonists and modulators. Knowledge of various determinants of PR action and their interactions with estrogen signaling to differentially modulate breast cancer biology should serve as a guide to the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.; ; SOURCE: Hari Singhal (hari_singhal@dfci.harvard.edu) - Geoffrey L Greene University of Chicago