Correlations between GREB1 Expression and Estrogen Receptor, HER2 Status in Human Breast Cancer.

Abstract

Abstract The two most common endocrine treatment modalities, anti-estrogen therapy and aromatase inhibitor therapy target estrogen receptor (ER) activation and estrogen (E2) biosynthesis, respectively. Although these therapies are effective in many patients with ER-positive tumors, prospective clinical trials have demonstrated that there exists a portion of patients with breast cancers that are initially responsive to endocrine therapy but subsequently relapse. Because of the lack of perfect correlation between ER and/or progesterone receptor (PR) status and patients who benefit from hormone therapy, there is a need to identify additional protein markers that would improve prediction of hormone response.Gene Regulated by Estrogen in Breast cancer 1 (GREB1) is regulated by estrogen (E2) in breast cancer and may serve as a candidate marker to predict response to endocrine therapy. The focus of this study was to define the significance of GREB1 protein expression in breast cancer and its correlation with estrogen receptor α status and epidermal growth factor receptor 2 (HER2) expression. Based on the query of 16 breast cancer expression array studies in the Oncomine Research database, GREB1 mRNA is expressed at greater levels in breast carcinomas than normal breast tissue (p value: 2.1E-5). In addition, GREB1 mRNA is significantly more commonly expressed in ER-positive breast cancer patients (n=1651) than ER-negative patients (n=670) (P value: 4.2E-5 ∼ 1.1E-34). Finally, GREB1 mRNA expression was observed to be lower in HER2+ breast cancer patients than in HER-2 – patients (p-value: 0.034). These mRNA expression data supported the hypothesis that GREB1 may have potential as a new biomarker for predicting E2-dependent and anti-E2 responsive breast cancers.Using a novel GREB1 monoclonal antibody generated by our laboratory, Immunohistochemical staining (IHC) was performed on a tissue microarrays containing invasive breast carcinomas from a cohort of 142 operable breast cancer patients (104 ER+ and 38 ER- cancers) with paired uninvolved tissue from the same patient. GREB1 protein was detected in both uninvolved normal tissue and ER+ breast cancer, but was absent in ER- tumors. Thus, IHC staining revealed GREB1 protein expression, predominantly localized in the cell nucleus, has a significant correlation with ER status (p-value <0.0001). Conversely, as observed in mRNA expression analysis, GREB1 protein levels inversely correlates with HER2 status (p-value <0.0001). Furthermore, decreased HER2 signaling caused by treatment with trastuzumab or lapatinib increased GREB1 (2-10 fold) and other ER target gene expressions, such as insulin receptor substrate 1 (IRS-1), insulin-like growth factor binding protein-4 gene (IGFBP4) and bcl-2 mRNA expression.These findings suggest, in addition to ER and PR, GREB1 may serve as a novel biomarker to distinguish patients who will benefit from tamoxifen therapy as well as identify anti-estrogen resistant breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2008.