Abstract
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 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. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and 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. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR-targeted therapies to the clinic.
Highlights
Progesterone receptor (PR) governs estrogen signaling in ER+/PR+ breast cancers by dictating chromatin binding of estrogen receptor alpha (ER) [1,2,3]and modulating the bioavailability of molecules needed for tumor growth [4]
Eighty percent of all ER+ breast cancers are positive for PR and while selective ER modulators (SERMs) are routinely used as adjuvant therapy in women with PR+ breast www.impactjournals.com/oncotarget cancers, relatively limited progress has been made in the development of effective PR-targeting therapies in the clinic
PR isoforms A and B differentially modulate the estrogen-dependent growth of breast tumor xenografts, underscoring that critical PR isoform-specific crosstalk occurs between ER and PR [16]
Summary
Modulating the bioavailability of molecules needed for tumor growth [4]. Gaps in the mechanistic understanding of the genomic actions of PR isoforms, ligand type (agonists and antagonists) and their intersection with estrogen signaling contribute to suboptimal utilization of PR as a potential therapeutic target in breast cancer. PR exists as two isoforms PRA and PRB, which are coded from two different transcription start sites of PR gene in the region 11q22-23 [5]. High PRA to PRB ratios in tumors predict poor patient survival and resistance to selective ER modulator (SERM) tamoxifen therapy [10]. PR isoforms A and B differentially modulate the estrogen-dependent growth of breast tumor xenografts, underscoring that critical PR isoform-specific crosstalk occurs between ER and PR [16]
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