Abstract 2921: Critical mediation of E2-induced apoptosis through c-Src in long-term estrogen deprived breast cancer cells

Abstract

Abstract Our previous publication showed that physiological concentrations of estrogen (E2) could trigger apoptosis of long-term E2 deprived breast cancer cells (MCF-7:5C) (Lewis et al. JNCI 2005; 97:1746-59). This new targeted strategy provides novel therapeutic approaches to endocrine resistant breast cancer. A phase II clinical trial reported that E2 provided a clinical benefit for aromatase inhibitor-resistant advanced breast cancer patients. However, only 30% of patients receive clinical benefit (Ellis MJ et al. JAMA 2009;302:774-80). This prompted us to investigate the mechanisms underlying E2-induced apoptosis to find strategies to increase the therapeutic responsiveness. c-Src is currently of interest, as it is an important adapter protein of ER in breast cancer cells. Here, we found that E2 stimulated c-Src phosphorylation in MCF-7:5C cells and 4-hydroxytamoxifen (4-OHT) could block this stimulation which demonstrated that E2 activated c-Src through ER. The specific inhibitor of c-Src, PP2, could block c-Src activation induced by E2. E2 rapidly activated growth pathways within minutes in MCF-7:5C cells and PP2 could block this non-genomic pathway. E2 was also able to activate Akt/MAPK pathways after 24 hour treatment which could be blocked by inhibition of c-Src. These data showed that c-Src mediated downstream signaling pathways of ER in MCF-7:5C cells. Characteristic E2-induced apoptosis occurred around 72 hour treatment with E2, unexpectedly, inhibition of c-Src could significantly block E2-induced apoptosis which implied that c-Src played a critical role in E2-induced apoptosis. Further examination through transcriptome analysis confirmed that E2 widely induced apoptosis-related pathways. Consistent with the biological experiments, PP2 could completely abolish the apoptosis pathways induced by E2. These data illustrate that c-Src acts as a critical molecule to mediate the downstream signaling of ER (including E2-induced apoptosis) in MCF-7:5C cells. It provides an important rationale for clinical trial with c-Src inhibitors in aromatase inhibitors resistant patients, especially avoiding in combination with physiological levels of E2. Acknowledgements This work (VCJ and JWG) is supported by the SU2C (AACR) Grant (SU2C-AACR-DT0409). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2921. doi:1538-7445.AM2012-2921