Abstract 5631: SRC1-driven network of transcription factors mediates hormone treatment resistance
Authors: Damir Vareslija, Alacoque Browne, Ailis Fagan, Nicola Cosgrove, Elspeth Ward, Leonie Young
Journal: Cancer Research (2017)

Abstract Despite the clinical benefit in treating ER positive breast cancer, hormone therapy resistance occurs in 40% patients leading to disease progression. Steroid receptor co-activator 1 (SRC1) enhances target gene transcription and has a critical role in breast cancer cell tumorigenicity. There is now key evidence that SRC1 is vital to the capacity of hormone-dependent tumors to adapt and overcome targeted therapy. Utilizing a genome wide multi omics sequencing of breast cancer patients and models, this study aimed to define the programs of SRC1 controlled transcriptional networks, identifying both interacting partners and downstream transcription factor (TF) targets that mediate the treatment resistant phenotype. RIME uncovered novel SRC1 interacting partners (including STAT1, PRMT1, and HDAC2) and associated TF partner networks in the hormone treatment resistant LY2 cells. In parallel, RNA-seq of LY2s with SRC1 stable knockdown revealed SRC1 regulated transcriptome networks identifying 1731 up regulated genes, including 153 TFs. SRC1 cistrome, characterized by ChIP-seq analyses was combined with motif binding analysis, to further validate 40 TFs directly regulated by SRC-1 and its interaction network. Dependence on SRC1 was confirmed through SRC-1 siRNA and CRISPR validation. Upon this discovery, validation and functional interrogation studies we identified a cadre of 4 TFs including E2F7, DEK, TRPS1 and SMARCA1 that execute SRC1 role in hormone treatment resistance. Functional analysis of this 4 gene TF network found it to be co-operating as a driver of hormone resistant cell by coupling activation of motility with stemness. TFs can reprogram resistant cells by reversing differentiation as demonstrated in the mammosphere, 3D acinar assays and CD24/44 flow cytometry analysis. This TF gene set is a significant predictor of poor recurrence free survival in hormone treated patients, supporting its role in increased metastatic risk in breast cancer and the clinical relevance of our findings. Furthermore, in an ER+ve PDX, established from resistant and treatment naïve patient, protein expression of the TF network members co-expressed with SRC1 and were only found in the hormone treatment resistant PDX models. This study highlights SRC1 regulated disease progression program in hormone treatment-resistant disease. Identified SRC1 interactome and its regulated transcriptome are active independent of its ER co-activator role. The SRC1 mediated TF network is involved in reprogramming of resistant cells, whose concerted activity is responsible for driving dedifferentiation of cells and enhancing their stem like and highly migratory tumor initiation population. This work provides key evidence on the mechanism of resistance in ER+ve hormone resistant cancer and has substantial implications both for the treatment of hormone dependent breast cancer and for identifying the mediators of metastatic potential. Citation Format: Damir Vareslija, Alacoque Browne, Ailis Fagan, Nicola Cosgrove, Elspeth Ward, Leonie Young. SRC1-driven network of transcription factors mediates hormone treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5631. doi:10.1158/1538-7445.AM2017-5631