Abstract 295: The cytosine deaminase APOBEC3B affects responses to therapy in estrogen receptor positive breast cancer cells

Abstract

Abstract Endocrine therapy, chemotherapy, or both represent the mainstay of therapy for estrogen receptor positive (ER+) breast cancer. However, acquired (secondary) drug resistance is a major clinical problem. We identified APOBEC3B (A3B), a DNA cytosine deaminase, as a source of DNA mutagenesis driving tumor evolution and contributing to poor clinical outcomes in several cancers by catalyzing genetic changes required for drug resistance and metastasis. A3B accounts for up to half of the mutational load in breast carcinomas expressing this enzyme. High levels of A3B correlate with poor clinical outcomes in tamoxifen treated patients. To evaluate the role for A3B in resistance to therapy, we used the ER+ MCF-7L breast cancer cell line. These cells have modestly elevated levels of endogenous A3B and we suppressed A3B levels by shRNA and enhanced levels by transduction. In vitro, alterations in A3B levels do not affect monolayer growth or cell doubling times. However, in vitro response to tamoxifen was prolonged in MCF-7L cells with suppressed A3B. In a xenograft model, MCF-7 cells with suppressed A3B remained responsive to tamoxifen for a longer period of time compared to wild type cells. Cells with overexpression of A3B had a very short period of tamoxifen suppression compared to wild-type cells. These data suggest high A3B levels are associated with a shorter period of response to tamoxifen. To evaluate the role for A3B in chemotherapy resistance, we treated cells with 5-fluorouracil. In contrast to tamoxifen therapy, cells with elevated A3B levels remained responsive to fluorouracil for longer periods of time compared to wild-type cells. Since A3B converts cytosine to uracil (C-to-U), we speculate that A3B enzymatic activity might enhance sensitivity to a fluoropyrimidine. Thus, the ability of A3B to affect therapeutic resistance in breast cancer may be dependent on the type and mechanism of drug treatment. Citation Format: Kelly S. LaPara, Emily Law, Reuben Harris, Douglas Yee. The cytosine deaminase APOBEC3B affects responses to therapy in estrogen receptor positive breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 295.