Abstract A053: ErbB3 downregulation enhances luminal breast tumor response to antiestrogens

Abstract

Abstract HER3/ErbB3 is required in luminal mammary epithelial cells (MECs). Given that breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that HER3/ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and frequent ERBB3 gene copy gains in clinical Luminal A/B breast cancers over other molecular subtypes. ErbB3 increased growth of luminal breast cancer cells, while ErbB3 targeting using U3-1287, a fully-human monoclonal anti-ErbB3 antibody, decreased three-dimensional colony growth, increased apoptosis, and decreased tumor growth in vivo. In response to the anti-endocrine fulvestrant, ErbB3 expression increased in clinical breast tumors, as did phosphatidylinositol 3-kinase (PI3K)/mTOR signaling. However, ErbB3 targeting with U3-1287 blocked compensatory PI3K/mTOR signaling in fulvestrant-treated tumor cells, transcriptional responses to fulvestrant, tumor cell survival and tumor growth. U3-1287 produced these effects in tumor cells with and without genetic PI3K pathway aberrations (PIK3CAH1047R, PIK3CAE545K, PTEN loss). Although fulvestrant increased phosphorylation of all ErbB family RTKs and insulin-like growth factor-1 receptor, phospho-RTK upregulation was not seen in tumors treated with U3-1287 and fulvestrant. Therefore, luminal breast cancer cells utilize ErbB3 for growth, survival, and to limit response to fulvestrant, thus defining a novel role for ErbB3 in breast cancer. Citation Format: Meghan M. Morrison, Jamie Stanford, Christian Young, David Vaught, Andrew Williams, michelle williams, Chuck M. Perou, Carlos L. Arteaga, Rebecca S. Cook. ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A053.