Abstract 404: Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer

Abstract

Abstract Basal-like or triple-negative breast cancer, if considered its own disease, would rank as the 5th leading cause of cancer deaths for women in the USA each year with ~10,000 deaths annually. Given the lack of drug-able targets expressed by TNBC tumors, few therapeutic options exist beyond currently utilized cytotoxic therapies, and the overall prognosis for these patients remains poor. The oncogenic PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility, and genomic instability. While multiple studies have demonstrated that basal-like or triple-negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined. In this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data in human breast tumors from TCGA (The Cancer Genome Atlas) including RNA expression, DNA copy number alterations, and protein expression. These analyses identified copy number alterations associated with PI3K activity in human breast tumors (n=1,031), including known and potentially novel drivers of PI3K signaling. Data from a genome-wide RNA interference (RNAi) screen were used to discriminate between essential and non-essential genes within identified amplicons. Integrating DNA copy number and RNAi analyses identified amplified SOX4 as a novel and essential regulator of PI3K/Akt signaling. Importantly, by analyzing protein expression data (n=733), we determined that SOX4 amplified tumors have increased activation of pAkt substrates. Moreover, depleting SOX4 levels in HCC38 and HCC1143, basal-like breast cancer cell lines with high PI3K activity and high SOX4 expression, demonstrated significant abrogation of p-Akt levels. This validated our in silico findings and confirmed the role of SOX4 in regulating PI3K pathway activity. To identify the potential mechanism(s) by which SOX4 mediates PI3K pathway activity, we performed genome-wide analyses of these cell lines following SOX4 inhibition. Transcriptomic profiling by RNA-sequencing, protein profiling by Reverse Phase Protein Array (RPPA) and Kinome profiling through multiplexed kinase inhibitor beads and mass spectrometry (MIB-MS) based approach identified TGFBR2, as a potential regulator of SOX4-mediated PI3K/Akt signaling. Further studies will elucidate the mechanism by which SOX4 modulates TGFBR2 expression and drives the oncogenic PI3K/Akt signaling pathway in basal-like breast cancer. Citation Format: Gaurav Mehta, Michael Gatza, Steve Angus, Gary Johnson. Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 404.