Abstract 3072: HER2 signaling affects SRC-3 phosphorylation and gene regulatory potential within the cistrome

Abstract

Abstract Steroid Receptor Coactivator-3 (SRC-3/AIB1) is a potent transcriptional coregulator for nuclear receptors and other transcription factors and is often amplified or overexpressed in tumors. The growth promoting effects of SRC-3 involve its ability to integrate extracellular signals into discrete patterns of gene expression. SRC-3 is regulated by various post-translational modifications, including multiple phosphorylations that define a combinatorial code that tailors SRC-3 activity in response to specific signaling stimuli. HER2 is a member of the ErbB receptor tyrosine kinase family of growth factor receptors and is often associated with cancer. Clinical studies show that breast cancer patients with tumors expressing high levels of both HER2 and SRC-3 have reduced disease-free survival, and SRC-3 phosphorylation is influenced by HER2. The current study seeks to define the effect of HER2 signaling events on SRC-3 activity in breast cancer cells. HER2 knock down using siRNA affects multiple kinase pathways, as evidenced by decreased AKT and c-Raf phosphorylation. HER2 knockdown causes the isoelectric point of SRC-3 to shift, suggesting that post-translational modification of SRC-3 is actively altered by HER2 signaling. Reduction of SRC-3 phosphorylation in HER2-depleted cells also was evident using a phospho-specific antibody to SRC-3. Expression microarray analysis revealed that many genes are altered by HER2 knockdown. Parsing the microarray with SRC-3 ChIP-seq data identified genes that are coordinately regulated by a HER2/SRC-3 signaling axis. Collectively, this work describes transcriptomic and cistromic mechanisms for oncogenic cooperation between HER2 and SRC-3 and identifies key genes that contribute to proliferation of breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3072. doi:1538-7445.AM2012-3072