Cytidine Deaminase Axis Modulated by miR-484 Differentially Regulates Cell Proliferation and Chemoresistance in Breast Cancer

Abstract There has been little study of how the evolution of chemoresistance in cancer affects other aspects of disease pathogenesis. Here, we show that an important chemoresistance axis driven by cytidine deaminase (CDA) also acts to suppress cell-cycle progression by regulating cyclin E–CDK2 signaling. We found that CDA was regulated by miR-484 in a gemcitabine-resistant model of breast cancer. Elevating miR-484 expression reversed the CDA effects, thereby enhancing gemcitabine sensitivity, accelerating cell proliferation, and redistributing cell-cycle progression. Conversely, elevating CDA to restore its expression counteracted the chemosensitization and cell proliferative effects of miR-484. In clinical specimens of breast cancer, CDA expression was frequently downregulated and inversely correlated with miR-484 expression. Moreover, high expression of CDA was associated with prolonged disease-free survival in studied cohorts. Collectively, our findings established that miR-484–modulated CDA has a dual impact in promoting chemoresistance and suppressing cell proliferation in breast cancer, illustrating the pathogenic tradeoffs associated with the evolution of chemoresistance in this malignant disease. Cancer Res; 75(7); 1504–15. ©2015 AACR.