Abstract
Objective: To study GRB7 protein expression in normal human tissues and breast and ovarian cancers, and determine its clinical significance. Results: GRB7 protein was expressed in multiple tissues, including myoepithelial cells of normal breast and fibroadenoma. Cytoplasmic GRB7 expression was seen predominantly in HER-2 positive and, to a lesser extent, triple negative breast cancer. Membrane localization of GRB7 was present in a subset of breast cancers with high cytoplasmic GRB7 expression. Univariate and multivariate analysis found that cytoplasmic GRB7 expression was associated with a negative progesterone receptor status, while membrane GRB7 expression was associated with a negative axillary nodal status. Membrane associated GRB7 expression was present in a subset of ovarian cancers with high cytoplasmic GRB7 expression. Membrane GRB7 expression displayed a trend towards improved recurrence free survival (RFS). Landmark analysis suggested an RFS advantage for ovarian cancers that had GRB7 membrane expression and survived beyond 27 months; GRB7 membrane expression in two or more cores (out of three) predicted an improved RFS. Membrane expression of GRB7 protein was observed in breast cancer cell lines with high GRB7 protein expression in vitro. Conclusion: GRB7 protein membrane expression may be associated with a better prognosis in breast and ovarian cancers. The favorable prognostic value of GRB7 protein membrane expression and its underlying mechanism is worthy of further investigation. Methods: Immunohistochemistry of normal human tissues, breast tissues of various pathologies, and clinically annotated ovarian cancers was performed to correlate the patterns of GRB7 expression with biomarkers or clinical outcome.
Highlights
Growth factor receptor-bound protein-7 (GRB7) protein is a 532 amino-acid adaptor molecule that lacks intrinsic enzymatic activity, but mediates signal transduction from multiple cell surface receptors to specific downstream signaling pathways inside the cell
GRB7 protein membrane expression may be associated with a better prognosis in breast and ovarian cancers
Lower GRB7 expression is seen in breast, fallopian tubes and pancreas, while almost no GRB7 expression was detected in the esophagus, lung, ovary or spleen
Summary
Growth factor receptor-bound protein-7 (GRB7) protein is a 532 amino-acid adaptor molecule that lacks intrinsic enzymatic activity, but mediates signal transduction from multiple cell surface receptors to specific downstream signaling pathways inside the cell. The consensus is that HER-2 positive breast cancer is generally associated with poor clinical outcome, we and others have found that GRB7 protein over-expression is a stronger independent adverse prognostic factor than HER-2 over-expression [9, 11]. The significance of GRB7 function is further supported by the laboratory findings that GRB7 over-expression facilitates HER-2 mediated signaling, breast cancer cell proliferation, and tumor formation in an animal model [4]. Knock down of GRB7 expression on the other hand, reduced the growth of HER-2 positive breast cancer cells in culture and as tumor xenografts in animal models [5, 12]. GRB7 expression is found to be an adverse prognostic factor for triple negative breast cancer (TNBC), both in vivo and in vitro [13, 14]. The prognostic significance of GRB7 expression has otherwise not been reported in ovarian cancer
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