Abstract 1112: Forced reduction of DSS1, a member of TREX2 complex, highly sensitizes chemotherapy to breast cancer cells in a BRCA2-independent manner

Abstract

Abstract [Introduction] DSS1 (deleted in split-hand/split-foot malformation 1) was originally identified as a BRCA2-associated/stabilizing protein. 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 (RFS); however, DSS1 expression per se was not correlated with other clinical parameters including cellular proliferation or tumor grade, suggesting that the level of DSS1 affected the sensitivity of DNA-damage agents in breast cancer cells (Rezano et al., 2013). It still remains unclear why the expression level of DSS1 is associated with chemosensitivity, because DSS1 has multifunctional properties regulating homologous recombination and RNA-mediated genomic stability. In this study, we investigated if the effect of DSS1 in chemosensitivity is influenced by two representative DSS1-associated molecules, BRCA2 and PCID2. [Methods] We established MCF7 overexpressing DSS1 (MCF7/DSS1) by retroviral transfection. DSS1, BRCA2, or PCID2 knockdown in MCF7 was performed using siRNA transfection. The susceptibility to the cytotoxic chemotherapy such as doxorubicin and paclitaxel in breast cancer cells was evaluated by flow cytometry to detect apoptosis and colony assay. In addition, we compared patient survival by dividing patients into high or low expression group of BRCA2 or PCID2 using cohort studies. [Results] BRCA2 depletion in MCF7/DSS1 did not alter the chemoresistance. Although DSS1 knockdown induced the downregulation of BRCA2, direct depletion of BRCA2 did not show marginal effect to chemosensitivity, suggesting that the enhancement of chemosensitivity by DSS1 knockdown was not related to BRCA2 expression. Importantly, over- and under-expression of PCID2 induced similar effect to chemosensitivity compared to those of DSS1. There was a trend that high PCID2 expression group in breast cancer patients showed worse prognosis in RFS. [Conclusion] DSS1 could be a molecular target to increase chemosensitivity, which is independent of BRCA2 expression. Rather, the transcription-coupled DNA damage induced by impaired TREX2 complex might be associated with induction of chemosensitivity. Citation Format: Kazuhiko Kuwahara, Naomi Gondo, Andri Rezano, Zhenhuan Zhang, Yukari Hato, Kiyotaka Kuzushima, Hiroji Iwata, Tatsuya Toyama, Eisaku Kondo. Forced reduction of DSS1, a member of TREX2 complex, highly sensitizes chemotherapy to breast cancer cells in a BRCA2-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1112. doi:10.1158/1538-7445.AM2017-1112