HER2 overexpression attenuates the antiproliferative effect of aromatase inhibitor in MCF-7 cells expressing aromatase

Abstract

We investigated the effect of HER2 overexpression on resistance to aromatase inhibitor letrozole in MCF-7 cells expressing aromatase (MCF-7/CA). MCF-7/CA cells overexpressing HER2 (MCF-7/CA pBMN-HER2) showed higher level of ER-mediated transcription activity upon androstenedione (AD) treatment as compared to vector control MCF-7/CA (MCF-7/CA pBMN-vec) cells and letrozole co-treatment did not effectively block AD-induced transcription. Inhibition of Akt and MAPK in MCF-7/CA pBMN-HER2 cells, resulted in the reduction of AD-induced transcription activities. MCF-7/CA pBMN-HER2 cells showed increased proliferation in the medium supplemented with AD as compared to MCF-7/CA pBMN-vec cells. Co-treatment of letrozole could not efficiently abrogate AD-mediated cell proliferation in MCF-7/CA pBMN-HER2 cells. MCF-7/CA pBMN-HER2 cells were also resistant to letrozole-induced apoptosis. ChIP assays revealed that MCF-7/CA pBMN-HER2 cells showed ligand-independent association of ERα, coactivators AIB1 and CBP to the promoter region of pS2 gene. Upon AD treatment, there were increased associations of ERα, AIB1 and CBP with pS2 promoter in MCF-7/CA pBMN-HER2 cells.