Abstract P3-06-14: DSS1 depletion is a promising strategy increasing chemosensitivity possibly independent of BRCA2 expression

Abstract

Abstract Background DSS1 (deleted in split-hand/split-foot malformation 1) was originally identified as a BRCA2-associated protein, and its downregulation results in the degradation of BRCA2. Some reports demonstrated that BRCA2 overexpression was correlated with histopathological grade III in sporadic breast cancers, implicating the involvement of BRCA2 overexpression in the proliferation rate of breast cancer cells. Because DSS1 is a stabilizer of BRCA2, we investigated whether altered expression of DSS1 was associated with malignant advancement of sporadic breast cancers. By comparison of DSS1 mRNA level, we reported that the high DSS1 expression groups in breast cancer patients showed worse prognosis in relapse-free survival; however, DSS1 expression per se was not correlated with other clinical parameters including cellular proliferation or tumor grade. Therefore, we hypothesized that breast cancer cells highly expressing DSS1 might be resistant to anti-cancer drugs, and compared chemosensitivity in overexpression or underexpression of DSS1 in breast cancer cells. Methods We established MCF7 overexpressing DSS1 (MCF7/DSS1) by retroviral transfection. DSS1 or BRCA2 knockdown in MCF7 was performed using siRNA transfection. The susceptibility to the cytotoxic chemotherapy such as doxorubicin and paclitaxel in breast cancer cells was analyzed by flow cytometry to detect apoptosis. Results MCF7/DSS1 showed more resistant to cytotoxic drugs compared with GFP-control MCF7 transfectants (MCF7/GFP). The percentages of apoptotic cells in MCF7/DSS1 and MCF7/GFP treated by doxorubicin were 40.2% and 12.0%, respectively. Conversely, depletion of DSS1 in breast cancer cells resulted in enhanced chemosensitivity compared to control cells. Although DSS1 knockdown induced the downregulation of BRCA2, BRCA2 depletion itself did not show such enhancement of chemosensitivity. Conclusion Consistent with the cohort study of sporadic breast cancers, we demonstrated that high expression of DSS1 increased resistance of breast cancer cells to cytotoxic chemotherapy in vitro. Conversely, DSS1 knockdown increased the susceptibility to these drugs in spite that BRCA2 depletion did not affect chemosensitivity. These results indicate that DSS1 could be a molecular target to increase chemosensitivity, which is independent of BRCA2 expression. Citation Format: Gondo N, Rezano A, Kuzushima K, Iwata H, Kuwahara K. DSS1 depletion is a promising strategy increasing chemosensitivity possibly independent of BRCA2 expression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-06-14.