Abstract
22076 Background: WWP1, a HECT type E3 ubiquitin ligase, is frequently amplified and overexpressed in breast cancer and may associated with positive ER status. IGF-1R is a tyrosine kinase growth factor receptor that has been linked to prognosis in a variety of malignancies. Activation of IGF-1R by autocrine, paracrine and endocrine stimulation via exposure to its activating ligand, insulin, leads to cell growth. Methods: Formalin-fixed, paraffin-embedded tissue sections from 122 cases of invasive mammary carcinoma (90 ductal carcinomas (IDC) and 32 lobular carcinomas (ILC) were immunostained by automated methods (Ventana Medical Systems Inc., Tucson, AZ) using mouse anti-human WWP1 (Novus Biologicals, Littleton, CO) and mouse anti-human IGF-1R antibody (sc-462; Santa Cruz Biotechnology, Santa Cruz, CA). Cytoplasmic immunoreactivity was semiquantitatively scored based on staining intensity and distribution for each protein and the results were correlated with morphologic and prognostic variables. The correlations between WWP1 and ER/IGF-1R were also analyzed in a panel of breast cancer cell lines by Western blot. WWP1 knockdown studies were used to test WWP1 regulation of ER and IGF-1R in ER positive breast cancer cell lines. Results: The adjacent benign epithelium was essentially negative for both proteins. Cytoplasmic WWP-1 immunoreactivity was observed in 53/122 (43%) tumors and showed a positive correlation with ER status (p=0.038). Cytoplasmic IGF-1R positivity was observed in 66/122 (54%) tumors and correlated with tumor subtype (61% IDC vs. 34% ILC, p=0.011) and ER status within the IDC subgroup (p=0.036). There was a significant co-expression of both proteins (p=0.001). The positive correlations between WWP-1 and ER/IGF-1R were also observed in a panel of breast cancer cell lines assessed by Western blot. WWP1 knockdown decreased the expression levels of both ER and IGF-1R in MCF7 and T47D cell lines. Conclusions: WWP-1 and IGF-1R proteins are overexpressed and are associated with each other and the ER+ phenotype in breast carcinoma. Further development of WWP-1 and IGF-1R as biomarkers for breast cancer management appears warranted. No significant financial relationships to disclose.
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