Abstract 2270: ATM is hyperactivated in triple-negative breast cancer tissues

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Triple-negative breast cancer (TNBC) represents a phenotype defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) expression. TNBCs are extremely aggressive and lack effective therapeutic targets. The DNA damage response is an active mechanism which prevents genetic instability and tumorigenesis. We have recently found the existence of active DNA damage responses in late stage breast cancer tissues. Here we report a critical role of the Ataxia-Telangiectasia-Mutated (ATM) kinase, a key transducer of DNA damage signals, in TNBC metastasis. By analyzing ATM activity in 169 cases of TNBC using immunohistochemistry, we found that ATM activity is enhanced in TNBCs, compared to 210 cases of non-TNBCs (P=0.003). Among the TNBC cases, 62.1% have lymph node metastasis, and ATM is hyperactive in these cases. As epithelial-mesenchymal transition (EMT) is associated with increased aggressiveness and metastatic potential, we also assessed the occurrence of EMT in these tissues. Interestingly, our results showed that tumors with higher ATM activity displayed increased expression levels of Snail, an early EMT marker (P=0.001). We also observed a strong correlation of ATM activity with up-regulation of another EMT marker, vimentin (P=0.015), and with reduction of characteristic epithelial markers, E-cadherin and cytokeratin (P=0.002 and P=0.036, respectively). Among the TNBC cases, the expression levels of activated ATM and Snail were significantly correlated with lymph node metastasis (P=0.008 and P=0.01, respectively). In our laboratory, we have extensively studied the molecular link between ATM and Snail, demonstrating that an active ATM-Snail pathway is essential for breast cancer metastasis. Taken together, our clinical data indicate that deficiency of ER, PR and HER2 may lead to hyperactive ATM and Snail, which contribute to high invasiveness and metastasis of TNBCs. 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 2270. doi:10.1158/1538-7445.AM2011-2270