Abstract LB-183: Y-box binding protein-1 YB-1 negatively regulates ERα expression accompanying by enhanced HER2/ErbB2 expression in breast cancer

Abstract

Abstract [Purpose] YB-1 containing a cold-shock domain is a potent oncogene for breast cancer (Bergmann et al., Cancer Res, 2005). Our previous studies have demonstrated that YB-1 plays pivotal roles not only in acquisition of global drug resistance and cell proliferation (Kuwano et al., Mol. Cancer Ther., 2004), but also in expression of HER2/ErbB2 in breast cancer cells (Fujii et al., Cancer Res., 2008) and stomach cancer cells (Shibata et al., Mol. Cancer Ther., 2013) in culture and clinical samples. In our present study, we first asked whether ERα affect YB-1-induced HER2 expression in breast cancer cells, and then asked whether YB-1 activation could be biostatistically linked to HER2 and/or ER expression in breast cancer patients. [Results] Is this study, we first examined the role of YB-1 in expression of HER2 and ERα by using ERα-positive and -negative breast cancer cell lines in culture, and we next examined whether YB-1 expression in nucleus could be biostatistically associated with HER2 or ERα expression by using clinical specimens of breast cancer. We observed novel findings as follows. [1] Knockdown of YB-1 markedly reduced HER2/ErbB2 expression in ERα positive human breast cancer cells, but only slightly reduced HER2/ErbB2 expression in ERα-negative breast cancer cells. [2] Nuclear YB-1 was forced expression by the tetracycline-induced YB-1/Tet-On system. Nuclear YB-1 expression enhanced HER2 expression and decreased ERα expression in ERα-positive cancer cells. By contrast, in ERα-negative breast cancer cells, there was no apparent increase in HER2 expression by YB-1. [3] Exogenous introduction of ERα cDNA resulted in suppression of HER2 expression dependent on YB-1 in ERα negative cells. Furthermore, treatment with tamoxifen stimulated YB-1-dependent HER2 expression in ERα-positive cells. [4] We further examined expression of YB-1, ERα, PgR and HER2 by immunohistochemical (IHC) analysis in clinical samples of breast cancer patients who had received no treatments by hormonal and chemical therapeutics. Based on expression levels of various factors, nuclear YB-1 expression was significantly correlated with HER2 expression, but negatively correlated with ERα expression in tumors of postmenopausal patients (n=114). By contrast, such significant association of YB-1 expression with ERα or HER2 expression was not seen in tumors of premenopausal patients (n=57). [Conclusions] YB-1 positively regulated HER2 expression and negatively ERα expression in ERα positive breast cancer cells, and the presence of ERα seems to be required for YB-1-dependent HER2 expression. Furthermore, in breast tumors of post-menopausal patients, nuclear localization of YB-1 was positively correlated with HER2 expression and negatively correlated with ERα expression. This study may contribute to further development of optimized endocrine- and HER2- targeted therapeutics against breast cancer. Citation Format: Tomohiro Shibata, Hiroto Izumi, Akihiko Kawahara, Satoshi Hattori, Chihiro Fukumitsu, Ryuji Takahashi, Kosuke Watari, Yuichi Murakami, Kimitoshi Kohno, Ken-ichi Ito, Masayoshi Kage, Michihiko Kuwano, Mayumi Ono. Y-box binding protein-1 YB-1 negatively regulates ERα expression accompanying by enhanced HER2/ErbB2 expression in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-183. doi:10.1158/1538-7445.AM2014-LB-183