Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer.

Steroid receptor coactivator 1 (SRC-1) interacts with nuclear receptors and other transcription factors (TFs) to initiate transcriptional networks and regulate downstream genes which enable the cancer cell to evade therapy and metastasise. Here we took a top-down discovery approach to map out the SRC-1 transcriptional network in endocrine resistant breast cancer. First, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was employed to uncover new SRC-1 TF partners. Next, RNA sequencing (RNAseq) was undertaken to investigate SRC-1 TF target genes. Molecular and patient-derived xenograft studies confirmed STAT1 as a new SRC-1 TF partner, important in the regulation of a cadre of four SRC-1 transcription targets, NFIA, SMAD2, E2F7 and ASCL1. Extended network analysis identified a downstream 79 gene network, the clinical relevance of which was investigated in RNAseq studies from matched primary and local-recurrence tumours from endocrine resistant patients. We propose that SRC-1 can partner with STAT1 independently of the estrogen receptor to initiate a transcriptional cascade and control regulation of key endocrine resistant genes

Integrative analysis of the SRC-1 transcriptional networks promoting endocrine resistance in breast cancer

Tamoxifen has been the gold standard treatment of oestrogen receptor positive breast cancer for over 40 years. While its use has significantly improved the outlook for breast cancer patients, up to 40% of patients relapse while on therapy. Steroid receptor co-activator 1 (SRC-1) is a master regulatory protein which is overexpressed in breast cancer. It is associated with high grade tumours, disease recurrence and is an independent predictor of poor disease-free survival. SRC-1 interacts with nuclear receptors and other transcription factors to initiate transcriptional networks and regulate downstream genes which enable the cell to evade therapy. Here, a top-down approach to map out the transcriptional network, regulated by SRC-1 in endocrine resistant breast cancer was taken. RNA-sequencing was performed to identify the transcriptional targets of SRC-1. Molecular characterization identified E2F7, NFIA, DEK, SMAD2, SMARCA1, ASCL1 and TRPS1 as SRC-1-regulated transcription factors/chromatin remodellers. Rapid immunoprecipitation of mass endogenous proteins was employed to uncover SRC-1 interacting partners. STAT1 was confirmed as an SRC-1-interacting transcription factor in endocrine resistant breast cancer. Extended analysis of the SRC-1 effector target gene network revealed genes important in activating cell cycle, proliferation and pathways in cancer. Concerted activity of the SRC-1-mediated network is responsible for driving the highly migratory and proliferative phenotypes of endocrine resistant breast cancer. Moreover, they play a significant role in regulating the undifferentiated tumour population. Upon clinical investigation, high expression of this SRC-1-regulated network is predictive of poor disease-free survival in a tamoxifen-treated patient population. This study provides important insight into a SRC-1-STAT1 complex initiating a transcriptional cascade and regulating key genes involved in endocrine resistance.</p

A Systems Biology Approach to Investigate Kinase Signal Transduction Networks That Are Involved in Triple Negative Breast Cancer Resistance to Cisplatin

Triple negative breast cancer (TNBC) remains a therapeutic challenge due to the lack of targetable genetic alterations and the frequent development of resistance to the standard cisplatin-based chemotherapies. Here, we have taken a systems biology approach to investigate kinase signal transduction networks that are involved in TNBC resistance to cisplatin. Treating a panel of cisplatin-sensitive and cisplatin-resistant TNBC cell lines with a panel of kinase inhibitors allowed us to reconstruct two kinase signalling networks that characterise sensitive and resistant cells. The analysis of these networks suggested that the activation of the PI3K/AKT signalling pathway is critical for cisplatin resistance. Experimental validation of the computational model predictions confirmed that TNBC cell lines with activated PI3K/AKT signalling are sensitive to combinations of cisplatin and PI3K/AKT pathway inhibitors. Thus, our results reveal a new therapeutic approach that is based on identifying targeted therapies that synergise with conventional chemotherapies