Abstract 803: HOXB7 functions as a co-activator of estrogen receptor 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 (SERM)-resistance in ERα positive breast cancer. Increased expression of HER family members can also directly alter cellular responses to tamoxifen, but the mechanism underlying the increased expression of the HERs is not clear. In this report we show that HOXB7 interacts with ERα, and together they bind to the promoter or enhancer regions of ERα-regulated genes to enhance their transcription activity. We found a number of novel HOXB7 binding sites at promoter regions, intron regions and adjacent to ER-binding sites in ER-regulated genes through HOXB7 ChIP on chiP using an Affymetrix promoter array. Potentially, HOXB7 and ERα may co-regulate about 84% of ERα-target genes. HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen. Overexpression of HOXB7 results in upregulation of HER2 and ERα target genes while knockdown of HOXB7 with siRNA in tamoxifen-resistant cell lines causes decrease of HER2 and ERα target genes expression and loss of tamoxifen resistance. Our data shows that to mediate upregulation of HER2 and ER-target genes occurring in tamoxifen resistance, the HOXB7-ERα complex recruits ERα coactivators and promotes HER2- and ER-target genes transcriptional activity through direct binding to the HER2 enhancer and regulatory regions of ER target genes. However, depletion of HOXB7 negatively affects the binding affinity of its cofactors to the HER2 enhancer element and ER-binding sites. Also, we found that miR196a might control HOXB7 expression; reducing miR196a levels in tamoxifen-resistant cells causes an increase of HOXB7 expression. Further, miRNA 196a is regulated by c-MYC which undergoes stabilization through the EGFR-HER2 signaling pathway. 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 hierarchy. Therefore, we have provided additional evidence that supports the thesis that functional antagonism of HOXB7 has the potential to circumvent tamoxifen resistance. 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 803. doi:1538-7445.AM2012-803