Functional dissection of the 11q14 amplicon in breast cancer implicates GAB2 as a driver oncogene

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4431 Previous studies have identified chromosome cytobands 11q12-q14 as a gene dense region harboring multiple independent amplicons involved in tumorigenesis. By combining array-based comparative genomic hybridization (array CGH) and fluorescence in situ hybridization (FISH) analysis on breast tumors (n=145) and cell lines (n=45), we have identified localized recurrent amplification at 11q14 that includes the docking protein GAB2, known to function in EGFR signaling. Although recent studies engineering GAB2 overexpression in mammary epithelial cells have implicated GAB2 as a candidate oncogene, its role in breast cancer progression when amplified is not well understood. We therefore used small interfering RNAs (siRNAs) to assess the phenotypic response to GAB2 knockdown in breast cancer cell lines harboring amplification of the 11q14 region. Knockdown of GAB2 using two independent siRNAs targeting GAB2 (in comparison to two mismatch control siRNAs) was associated with decreased cell proliferation in the two cell lines tested (MDA-MB-468 and SUM 52) with GAB2 amplification and/or overexpression. Moderate effects on proliferation were also observed in a cell line (BT474) harboring ERBB2 amplification, consistent with the possibility that GAB2 can function downstream of ERBB2. Our studies implicate amplification/overexpression of GAB2 as contributing to the high proliferation rates of breast cancer cells, and suggest the potential utility of targeting GAB2 in breast tumors with amplification or overexpression.