Abstract P3-04-17: Global transcriptional repression by the coactivator SRC-1 mediates disease progression in treatment-resistant breast cancer

Abstracts: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, Texas Despite the effectiveness of endocrine therapy in treating estrogen receptor (ER) positive breast cancer, nearly 40% of breast cancer patients may develop resistance which can lead to metastatic disease progression. Steroid receptor co-activator-1 (SRC-1), a key regulator of ER signalling, is overexpressed in 35% of breast cancer patients and is strongly associated with the development of endocrine resistant metastasis(1). Recent studies highlighted the ability of SRC-1 to also act as transcriptional repressor. SRC-1 can therefore bi-directionally regulate gene expression to promote the resistant phenotype (2). 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 identified 736 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 distinct differentially methylated regions specific to SRC-1 repressed target genes. Mechanistic studies in endocrine resistant cells revealed a role for methylation proteins, DNMTs and MBD, in SRC-1 directed repression. Through combined analysis of our global sequencing data we identified a network hub of five differentiation genes directly repressed by SRC-1. High expression of this signature predicts enhanced recurrence free survival in tamoxifen treated patients (n=335, p=0.032 ). A reduction in expression of these genes was shown to have functional output on proliferation, migration and mammosphere formation. Finally, we use tumour explant models to show that targeting DNA methylation can be used to reverse the SRC-1 driven suppression of this differentiation hub. Here we report a novel mechanism by which SRC-1 may be driving endocrine resistant tumorigenesis. Our genome-wide discovery approach revealed a global epigenetic re-programming pathway whereby concerted differential DNA methylation is potentiated by the activation of SRC-1 in the presence of tamoxifen in the endocrine resistant setting. This study suggests that therapeutic strategies of combined targeted epigenetic therapy with estrogen deprivation could be a successful strategy to prevent acquired resistance to endocrine therapy. Citation Format: Ward E, Vareslija D, Fagan A, Hill A, Young L. Global transcriptional repression by the coactivator SRC-1 mediates disease progression in treatment-resistant breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-17.