Abstract P6-02-03: SUMO Inhibitors affect tumorigenesis of novel breast cancer xenograft model

Abstract

Abstract A novel basal breast cancer cell line IOWA-1T was derived from chemotherapy resistant locally advanced breast cancer tumor. The cells rapidly form large, skin-eroding xenografts in nude mice. The SUMO inhibitor anacardic acid (AA) effectively cleared CD44+/hi/CD24-/low cancer stem cell (CSC) population in IOWA-1T and BT-20 basal cancer cell lines and delayed tumor outgrowth of basal cancer xenografts. The effect of SUMO inhibitors to clear the CSC population was dependent upon the SUMO unconjugated form of TFAP2A (Bogachek MV et al, Cancer Cell, 2014). Herein we show that tumors that eventually form from IOWA-1T xenografts in mice treated with AA are not capable of developing secondary xenografts, confirming eradication of the CSC population by SUMO inhibitors. As further mechanistic evidence for the SUMO pathway, transient knockdown of UBC9 and PIAS1 SUMOylation enzymes repressed CD44 expression and increased tumor free and overall survival in mice inoculated with IOWA-1T xenografts. Furthermore, CD44 downregulation was demonstrated in IOWA-1T cells after treatment in vitro with UBC9 inhibitor PYR-41 and PIAS1 inhibitor NSC-207895. Overall survival of mice with IOWA-1T xenografts was increased to 43±0.5 and 39±2 days with PYR-41 and NSC-207895 i.p. injections, respectively, compared to a vehicle treated control group 33±1 days (p<0.05). By contrast, doxorubicin treatment was not able to extend survival of mice with IOWA-1T xenografts. These findings establish the class of SUMO inhibitors as potential therapeutic drugs that eliminate the breast CSC population and may be effective in basal breast cancer cases resistant to conventional chemotherapy. Citation Format: Maria V Bogachek, Jung M Park, James P De Andrade, Mikhail V Kulak, Jeffrey R White, Tong Wu, Philip M Spanheimer, George W Woodfield, Thomas B Bair, Alicia K Olivier, Ronald J Weigel. SUMO Inhibitors affect tumorigenesis of novel breast cancer xenograft model [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-02-03.