Abstract 745: HOXB7 renders breast cancer resistant to tamoxifen through activation of the HER2 pathway

Abstract

Abstract Multiple factors, including long term treatment with tamoxifen, are involved in the development of selective estrogen receptor modulator (SERM) resistance of ERα positive breast cancer. It is well known in the endocrinology field that increased levels of ErbB/HER family members can also directly alter the cellular response to tamoxifen, but the mechanisms underlying increased expression of ErbB/HERs are not clear. In this studyreport we identifiedfound a number of HOXB7- specific binding sites throughout the genome in responsewith reaction to estrogen, through HOXB7 Chip on chip assay. We show that HOXB7 interacts with ERα and together they it bind to theharbors regulatory elements of ERα- regulated genes to enhance their transcription activity. Enforced expression of HOXB7 increases expression of ERα- regulated genes while knockdown of HOXB7 with siRNA reduces their expression. In addition, our work demonstrates that in order to mediate upregulation of HER2 in tamoxifen resistance, the HOXB7-ERα complex recruits ERα coactivators and promotes HER2 transcription activity through direct binding to the HER2 enhancer region. However, depletion of HOXB7 negatively affects the binding affinity of its cofactors to the HER2 enhancer element. Higher expression levels of HOXB7 significantly correlates with poorer disease free survival in ERα- positive breast cancer patients on adjuvant tamoxifen monotherapy. These findings implicate overexpression of HOXB7 as a key event in the initiation and maintenance of tamoxifen resistance. These studies suggest that HOXB7 acts as a key regulator orchestrating two major groups of target molecules, ERα and HER2, in the oncogene hieeirarchy. Therefore, fFunctional antagonism of HOXB7 has the potential tocould circumvent tamoxifen resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 745. doi:10.1158/1538-7445.AM2011-745