Tumor and Stem Cell Biology Cross-talk between HER2 and MED1 Regulates Tamoxifen Resistance of Human Breast Cancer Cells

Despite the fact that most breast cancer patients have estrogen receptor (ER) a-positive tumors, up to 50% of the patients are or soon develop resistance to endocrine therapy. It is recognized that HER2 activation is one of themajormechanisms contributing to endocrine resistance. In this study,we report that theER coactivatorMED1 is a novel cross-talk point for the HER2 and ERa pathways. Tissue microarray analysis of human breast cancers revealed that MED1 expression positively correlates most strongly with HER2 status of the tumors. MED1 was highly phosphorylated, in a HER2-dependent manner, at the site known to be critical for its activation. Importantly, RNAi-mediated attenuation of MED1 sensitized HER2-overexpressing cells to tamoxifen treatment. MED1 and its phosphorylated form, but not the corepressors N-CoR and SMRT, were recruited to the ERa target gene promoter by tamoxifen in HER2-overexpressing cells. Significantly, MED1 attenuation or mutation of MED1 phosphorylation sites was sufficient to restore the promoter recruitment of N-CoR and SMRT. Notably, we found that MED1 is required for the expression of not only traditional E2-ERa target genes but also the newly described EGF-ERa target genes. Our results additionally indicated thatMED1 is recruited to theHER2 gene and required for its expression. Taken together, thesefindings support a key role forMED1 inHER2-mediated tamoxifen resistance and suggest its potential usage as a therapeutic target to simultaneously block both ERa and HER2 pathways for the treatment of this type of endocrine resistant breast cancer. Cancer Res; 72(21); 5625–34. 2012 AACR.