Abstract
Abstract Mounting clinical data implicates progesterone and its receptor (progesterone receptor; PR) in breast cancer progression. Upon diagnosis, nearly 70% of breast cancers express PR and the estrogen receptor (ER). In contrast, only 7-10% of normal luminal epithelial cells express ER and PR. Mitogenic protein kinases (MAPK, ck2) known to modify and activate PR have been shown to be dysregulated in breast cancer. This creates a context wherein PR is inappropriately activated by aberrant kinases in the absence of hormones. We hypothesize that ck2-dependent phosphorylation of PR Serine 81 (Ser81) “redirects” the modified receptor to a distinct subset of target genes, including STAT5A, a gene required for mammary gland development and key to mediating inflammatory/interferon responses. Microarray data sets were analyzed using Gene Set Enrichment Analysis (GSEA) from progestin (R5020)-treated T47D breast cancer cells stably expressing either wt or Ser81 phospho-mutant PR (S79/81A PR). GSEA revealed that genes from multiple JAK/STAT, inflammatory and interferon-regulated gene sets were significantly enriched in our T47D-wt PR dataset. Enrichment of these gene sets was lost in cells lacking PR Ser81 phosphorylation (S79/81A PR), suggesting that Ser81 phosphorylation is necessary for their PR-dependent regulation. Leading Edge (LE) analysis revealed a significant enrichment in inflammatory/interferon-regulated pathways, again dependent upon PR Ser81 phosphorylation. Regulation of individual genes identified as being highly associated with the overlapping gene sets (LE gene list) was impaired in cells expressing S79/81A PR relative to cells expressing wt PR. Of note, many of these genes are transcriptional targets of interferon signaling pathways and key mediators of inflammation (i.e. IFITs, STATs, CXCL10, CXCL2, OAS1/2). Moreover, CEAS (cis-regulatory element annotation system) analysis of a publically available PR ChIP-chip data set (obtained from T47D breast cancer cells treated with progesterone) revealed significant enrichment of STAT5 binding motifs (GAS sites) within PR binding sites. Finally, using ChIP analysis we identified coordinate PR and STAT5 binding at key PR Ser81-regulated target genes; recruitment failed to occur in PR S79/81A-expressing cells. Cumulatively, these data support a model of coordinate regulation between PR and STAT5 on a select subset of Ser81 phosphorylation-dependent PR target genes. Many any of these genes are involved in cellular immune/inflammatory responses. We predict that direct interaction between STAT5 and PR at enhancer regions drives inflammatory gene programs in breast cancer. Understanding cross-talk between PR and inflammation is critical to developing better treatments, and could expose a novel mechanism through which PR drives early events in breast cancer development and progression that may be exploited using novel PR-based endocrine therapies. Citation Format: Christy R. Hagan, Todd P. Knutson, Carol A. Lange. Progesterone receptor promotes inflammatory gene programs in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1868A. doi:10.1158/1538-7445.AM2015-1868A
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