O2-15-2 - Y-Box Binding Protein-1 Activation May Modify the Responses to Endocrine and Her2-Targeted Therapeutics in Breast Cancer

Abstract

Purpose: YB-1 is a potent oncogene for breast cancer (Bergmann et al. Cancer Res, 2005). Our previous studies have demonstrated that nuclear localization of YB-1 plays pivotal roles in HER2/ErbB2 expression in breast cancer as well as in stomach cancer in vitro and in patients. In our present study, we first asked whether YB-1-induced expression of HER2 gene could be closely coupled with the absence or presence of ERα, and then asked whether YB-1 activation could be biostatistically linked to HER2 and/or ER expression in breast cancer of pre-menopausal and post-menopausal patients.Results: [1] In breast cancer cell lines: YB-1 knockdown by its cognate siRNA resulted in marked reduction of HER2 expression in ERα(+) breast cancer cells, but not in ERα(-) cells; and YB-1 overexpression in nucleus resulted in induction of HER2 expression accompanying by decreased expression of ERα; and ERα overexpression by exogenous transfection of its cDNA induced suppression of YB-1 dependent HER2 expression; and also the functional blockage of ERα by tamoxifen resulted in increasing expression of HER2. [2] In immunohistochemical analyses of clinical samples: In tumors from post-menopausal patients (n = 114), nuclear YB-1 expression was positively associated with HER2 expression, but negatively associated with ERα/PgR expression; however in tumors from pre-menopausal patients (n = 57), nuclear YB-1 expression was not significantly associated with ERα/PgR or HER2 expression.Conclusion and Discussion: Based on our basic and clinical study, YB-1 activation plays an essential role in expression of HER2/ErbB2, depending upon the absence or presence of ERα in breast cancer. The cross-talk of ERα and HER2 through activated YB-1 may thus specify biological characteristics in breast cancers luminal A, luminal B (HER2+), luminal B (HER2-), HER2 disease and triple negative. This study may propose an idea how endocrine and HER2-targeted therapeutics are mutually optimized against breast cancer.