Abstract
10617 Background: Triple-negative (TN) breast cancers are so-called as they lack expression ER and PR and overexpression of HER-2. Unlike other subgroups of patients with breast cancer, targeted therapy is currently unavailable for these patients. Consequently, the only systemic therapy for TN patients is chemotherapy. The aim of this study was to investigate the use of c-src as a potential target for the treatment of patients with TN breast cancer. Methods: Src immunoreactivity was determined using TMAs in 87 randomly-selected TN and 93 non-TN breast cancers diagnosed at St Vincent's Univ Hospital over the period 2002-2006. In vitro proliferation assays were performed to test combinations of dasatinib and cytotoxic drugs in breast cancer cell lines. Synergy analysis was performed using the Tchou and Talalay equation on CalcuSyn software. Results: 83/87 (95%) of TN cancers were positive for src compared to 78/93 (84%) of non-TN samples (p = 0.012, chi square test). Similarly, membrane staining for src was found more frequently in TN than in non-TN samples (74% vs 38%, p < 0.0001, chi square test). Using 9 different breast cancer cell lines in culture, dasatinib (an inhibitor of c-src) blocked growth in 3 out of 5 TN cell lines with IC50 < 1 μM (i.e, in MDA-MB-231, HCC-1143, HCC-1937) but in only 1 out of 4 HER2 amplified cell lines. Dasatinib combined with docetaxel displayed moderate synergy in MDA-MB-231 and HCC-1937 cells (CI < 0.9), but was antagonistic in HCC-1143 cells (CI > 1.1). Combined treatment with dasatinib and cisplatin was synergistic in the three dasatinib sensitive cell lines (CI < 0.9). In MDA-MB-231 and HCC-1143 cells, combined treatment with dasatinib and 5′-DFUR displayed synergy (CI < 0.9), whereas the combination was additive in HCC-1937 cells (CI = 0.98). Conclusions: We conclude that a combination of dasatinib and cisplatin is a potential new treatment for patients with TN-negative breast cancer. Acknowledgements: The authors wish to thank Science Foundation Ireland (08/SRC/B1410) and the Health Research Board (CSA/2007/1) for funding this work. No significant financial relationships to disclose.
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