Abstract 3147: HER2 gene amplification and CDC25A overexpression in human breast cancer

HER2 gene amplification/overexpression has been identified in 10-34% of invasive breast cancers and correlates with reduced disease-free and overall survival. The HER2-targeted therapy with trastuzumab decreases the risk of relapse and prolongs survival. Resistance to trastuzumab is a significant barrier to the effective HER2-positive breast cancer treatment: response rate ranges from 20-35%, underlining that HER2-positive breast cancer is hardly a homogeneous disease and, more importantly, that other HER2-related pathways need to be unveiled. Recent studies provided evidence that HER2 overexpression increases skin tumorigenesis through CDC25A maintenance: HER2 suppresses DNA damage-induced checkpoint activation through lack of CDC25A degradation. CDC25A phosphatase, an essential component of the cell cycle machinery, is also a key player in integrating the specific signals of checkpoint control in response to DNA damage. CDC25A misregulation contributes to genomic instability and cancer development. Oncogene activation during early stages of tumor development causes DNA replication stress resulting in the DNA damage response (DDR) induction and the selection of cells defecting in their DDR could lead to malignant progression. Accordingly, CDC25A overexpression in primary human breast cells promotes the DDR alteration, increasing the chances of tumorigenic conversion by enhancing genomic instability at common fragile sites. The aim of our work was to verify a relation between HER2 and CDC25A in human breast cancer. To this end HER2 amplification and CDC25A overexpression were determined in 220 breast cancer patients. We found a statistically significant correlation between HER2 gene status and CDC25A expression (p=0,000): 64,4% of HER2 amplified tumours show CDC25A overexpression and 75,5% of tumours with no HER2 amplification do not overexpress CDC25A. Furthermore HER2 status and CDC25A expression significantly correlate with prognosis (p=0,003 and p=0,047 respectively). A mortality risk stratification was identified when four different combinations of HER2 status and CDC25A expression were evaluated for their relative effect on survival: the group with the highest mortality was the one in which breast carcinomas showed both HER2 amplification and CDC25A overexpression (p=0,019). Our in vitro studies demonstrate that HER2 can stabilize CDC25A protein levels in breast cancer cell lines, through PI3K-AKT pathway: decreased HER2-mediated signaling by HER2 inhibitors resulted in CDC25A decreased expression; remarkably CDC25A inactivation by specific inhibitor can restore response to IR-induced DNA damage in HER2-positive, both trastuzumab sensitive and resistant, breast cancer cell lines. These findings suggest a CDC25A role for a more specific characterization of HER2-positive breast cancers, warranting further study of its potential as therapeutic target in combination with HER2. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3147. doi:10.1158/1538-7445.AM2011-3147