Abstract 3177: Cas overexpression in breast cancer confers resistance to chemotherapy by evading apoptosis and overcoming G0/G1 arrest

Abstract

Abstract Breast cancer patients treated with chemotherapy often develop resistance, resulting in highly aggressive tumors that are insensitive to drugs. Elucidating the mechanisms by which cancer cells are able to escape drug-induced apoptosis is thus paramount for developing better approaches to treat and cure breast cancer. Adriamycin is an anthracycline that is regularly used for treatment of breast cancer. Upon exposure to adriamycin, sensitive cells undergo cell death. However, as is the case for many chemotherapeutic drugs, cancer cells frequently develop resistance to adriamycin. We have previously reported that MCF-7 breast cancer cells that overexpress the adaptor molecule p130Cas (Cas) are resistant to adriamycin, whereas MCF-7 cells with endogenous levels of Cas are sensitive to the drug (Ta et al., 2006 Cancer Research). This is consistent with reports showing that high expression of Cas correlates with poor relapse-free and overall survival (Van der Flier et al., 2000 JNCI). Our group has shown that Cas overexpression results in significantly less apoptosis in the presence of adriamycin, and that, the kinase activities of c-Src and PI3K are required for this protection from apoptosis. Furthermore, we show that there is a significant increase in AKT activation when Cas-overexpressing cells are treated with adriamycin. Interestingly, while MCF-7 cells expressing endogenous levels of Cas exhibit a G1 arrest upon adriamycin treatment, the more resistant Cas-overexpressing cells effectively transit through G1 and accumulate in S-phase. This suggests that overexpression of Cas may allow damaged cells to bypass the G0/G1 DNA damage checkpoint. Indeed, both MCF-7 cells expressing either endogenous or elevated levels of Cas show similar degrees of DNA damage when treated with adriamycin, as measured by phospho-histone H2AX. We saw a similar progression through the G0/G1 checkpoint in Cas-overexpressing MCF-7 cells under conditions of serum deprivation, suggesting that high Cas expression may have a relatively global effect on G0/G1 cell cycle checkpoints in response to distinct cellular insults. Based on these data, we hypothesize that Cas overexpression enables breast cancer cells to proceed through the G0/G1 cell cycle arrest induced by conditions of stress, such as DNA damage or nutrient deprivation. Future studies will focus on determining mechanisms by which Cas overexpression allows cancer cells to bypass these cell cycle checkpoints. By gaining a better understanding of how cancer cells are able to adapt and continue to proliferate in an unfavorable environment, and develop resistance to chemotherapy, this study will further the development of better strategies for targeting this aggressive cell population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3177.