Abstract PD05-10: HOXB7 as a Key Regulator in the Development of Tamoxifen Resistance

Abstract

Abstract Multiple factors including long term treatment with tamoxifen are involved in the development of selective estrogen receptor modulator 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 report we show that HOXB7 is an ERα responsive gene and the downregulation of HOXB7 expression by estradiol is abrogated by tamoxifen in MCF7 cells. HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERα signaling. EGFR and HER2 expression is upregulated by overexpression of HOXB7, while knockdown of HOXB7 with siRNA in tamoxifen-resistant cell lines causes decrease of EGFR and HER2 expression and loss of tamoxifen resistance. In addition, our work demonstrates that to mediate upregulation of EGFR and HER2, HOXB7 binds to ER-alpha and promotes HER2 transcription activity through direct binding to the HER2 enhancer region by competing with other cofactors. Also, HOXB7 enhances EGFR transcription activity via binding to EGFR promoter region. However, depletion of HOXB7 affects the binding affinity of HOXB7 and the cofactors to the HER2 enhancer element. Higher expression levels of HOXB7 significantly correlated 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 in the oncogene heirarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-10.