title: 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.
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, China.
authors: Fu-Gui
authors: FG
authors: Ye
authors: Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, China. xinhu@fudan.edu.cn songchuangui@yahoo.com.
authors: Chuan-Gui
authors: CG
authors: Song
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Zhi-Gang
authors: ZG
authors: Cao
authors: The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
authors: Chen
authors: C
authors: Xia
authors: Department of Breast Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, China.
authors: Dan-Na
authors: DN
authors: Chen
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Li
authors: L
authors: Chen
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Shan
authors: S
authors: Li
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Feng
authors: F
authors: Qiao
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Hong
authors: H
authors: Ling
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Ling
authors: L
authors: Yao
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. xinhu@fudan.edu.cn songchuangui@yahoo.com.
authors: Xin
authors: X
authors: Hu
authors: Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Zhi-Ming
authors: ZM
authors: Shao
mesh_terms: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000502:physiology*; D016016:Proportional Hazards Models; D034622:RNA Interference; D000093542:Gemcitabine
chemical_list: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D019927:Cyclin E; C572386:MIRN484 microRNA, human; D035683:MicroRNAs; D003841:Deoxycytidine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D003564:Cytidine Deaminase; D000093542:Gemcitabine