Abstract P3-04-16: Steroid receptor co-activator 1 mediation of cancer cell reprogramming in endocrine resistant breast cancer
Authors: A Browne, A Fagan, D Vareslija, E Ward, A Hill, L Young
Journal: Cancer Research (2017)

Abstract Cancer cells undergo dynamic and frequently reversible modifications and this cellular plasticity permits reprogramming in response to long term endocrine treatment. A well-established theory, the cancer stem cell theory; suggests that within an ER positive tumour cell population are a small number of stem cells which are capable of infinite self-renewal and are insensitive to treatment with standard endocrine regimes. However, emerging reports that pluripotent cells can be generated from adult somatic cells (Takahashi, 2007) alludes to an alternate mechanism for cancer cells to reprogramme and evade endocrine treatment. To investigate the role of tamoxifen in promoting cellular reprogramming and endocrine resistance in breast cancer, we isolated single luminal A breast cancer CD24+CD44- clones from endocrine sensitive MCF-7 cells. The clones were expanded in the presence and absence of tamoxifen. Extensive profiling of cells following long-term exposure to tamoxifen revealed a resistant phenotype similar to that reported in other established models. Steroid receptor co-activator 1 (SRC-1) is a master regulatory protein which has been shown to be central to the development of endocrine resistance. The mechanisms of which are still poorly understood (Walsh et al., 2012). Utilising genome-wide transcriptomic sequencing this study investigated whether SRC-1 can regulate transcriptional networks which mediate reprogramming in individual cells to induce survival adaptability and drug resistance in breast cancer. RNA-sequencing was carried out in a model of endocrine resistance (shNon-Targeting versus shSRC-1). There were 1,731 genes up-regulated by SRC-1, of which 153 were identified as transcription factors (TFs)/chromatin remodellers. Combining the transcriptomic profiling with ChIP-sequencing we identified a transcriptional network pertinent to SRC-1. Molecular characterisation identified E2F7, NFIA, DEK, SMAD2, SMARCA1, ASCL1 and TRPS1 as key drivers of SRC-1 mediated endocrine resistance. Each TF was confirmed as a direct target of SRC-1, via promoter specific binding and were found to be drivers of endocrine resistant cell migration. Furthermore, all TFs were necessary in mammosphere formation and their promotion of cellular de-differentiation was observed by 3D acinar organisation and flow cytometry. To elucidate the core TFs required for cancer cell reprogramming, their effect on the pioneer reprogramming TFs (OCT4, SOX2, cMYC and KLF4) was investigated. SMAD2, SMARCA1, ASCL1 and TRPS1 have emerged as pivotal regulators of endocrine resistant cell reprogramming. This study has unravelled an SRC-1-mediated TF network responsible for promoting the cellular reprogramming of breast cancer cells. Concerted activity of this network is responsible for driving de-differentiation of cells and enhancing their stem-like, highly migratory and proliferative tumour initiation population. This study provides important information regarding the mechanism of cellular reprogramming in ER positive endocrine resistant cancer and may lead to potential novel therapeutic targets. Citation Format: Browne A, Fagan A, Vareslija D, Ward E, Hill A, Young L. Steroid receptor co-activator 1 mediation of cancer cell reprogramming in endocrine 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 P3-04-16.