Abstract 861: Global transcription factor repression by the coactivator SRC-1 mediates disease progression in endocrine-resistant breast cancer

Abstract

Abstract Despite the clinical utility of endocrine therapies to treat ER positive breast cancer, 40% of patients eventually develop resistance, leading to disease progression. Steroid receptor co-activators have been described as “the powerhouses of transcription” with a role in mediating hormone receptor responsiveness. There is now substantial evidence that steroid receptor coactivator-1 (SRC-1) is central to the ability of endocrine tumours to adapt and overcome targeted therapy thereby facilitating metastatic disease progression. Recent work highlighted the potential ability of SRC-1 to also act as transcriptional repressor that can bi-directionally regulate genes that help it promote the resistant phenotype. This study employed a genome-wide multi-omics sequencing approach to determine the SRC-1 repression signature in endocrine resistance and elucidate the mechanism by which SRC-1 mediates this repression. RNA-sequencing was used to investigate the transcriptional network affected by SRC-1 in an endocrine resistant cell line model. This approach identified 1,495 genes significantly downregulated by SRC-1, with common functional pathways such as differentiation, cell morphogenesis and extracellular matrix enriched in the gene set. Parallel global methylation sequencing analysis revealed methylation as a possible mechanism by which SRC-1 was repressing target genes, which was confirmed with mechanistic studies utilising 5-AZA-2’-deoxycitidine. Through combined analysis of our global sequencing data we identified a SRC-1 regulated transcriptional hub of differentiation genes, that have protective roles in normal and treatment- sensitive breast cancer cells and which associate with poor disease-free survival in breast cancer patients. Furthermore, our work demonstrated that SRC-1 can re-programme cells to become poorly differentiated by supressing this normally protective transcriptional hub, and thereby promote aggressive endocrine resistant phenotype. Here we report a novel mechanism by which SRC-1 can drive endocrine resistant tumorigenesis. Our genome-wide discovery approach revealed an epigenetic re-programming pathway, whereby concerted differential DNA methylation is potentiated by the activation of SRC-1 in the endocrine resistant setting. This study suggests that therapeutic strategies of combined targeted epigenetic therapy with estrogen deprivation could be successful strategy to prevent acquired resistance to endocrine therapy. Citation Format: Damir Vareslija, Elspeth Ward, Ailis Fagan, William Gallagher, Arnold DK Hill, Leonie S. Young. Global transcription factor repression by the coactivator SRC-1 mediates disease progression in endocrine-resistant breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 861.