title: Competing endogenous RNA networks of CYP4Z1 and pseudogene CYP4Z2P confer tamoxifen resistance in breast cancer.
abstract: Patients with estrogen receptor α (ERα)-positive breast cancer can be treated with endocrine therapy using anti-estrogens such as tamoxifen; nonetheless, patients often develop resistance limiting the success of breast cancer treatment. The potential mechanisms remain elusive. In detail, many miRNAs have been associated with breast cancer tamoxifen resistance, but no studies have addressed the role of miRNA-mediated competitive endogenous RNAs network (ceRNET) in tamoxifen resistance. The ceRNET between CYP4Z1 and pseudogene CYP4Z2P has been revealed to promote breast cancer angiogenesis. However, its function in tamoxifen resistance remains unclear. Here we report CYP4Z1 and CYP4Z2P were downregulated in MCF-7 cells compared with tamoxifen-resistant MCF-7-TamR cells. Enforced upregulation of CYP4Z1- or CYP4Z2P-3'UTR level renders MCF-7 Cells resistant to tamoxifen. We find that overexpression of CYP4Z1- or CYP4Z2P-3'UTR enhances the transcriptional activity of ERα through the activation of ERα phosphorylation. Furthermore, we find that CYP4Z1- and CYP4Z2P-3'UTRs increase ERα activity dependent on cyclin-dependent kinase 3 (CDK3). Reporter gene and western blot assays revealed that CYP4Z1- and CYP4Z2P-3'UTRs act as CDK3 ceRNAs. More importantly, the blocking of CYP4Z1- and CYP4Z2P-3'UTRs reversed tamoxifen resistance in MCF-7-TamR cells. Our data demonstrates that the ceRNET between CYP4Z1 and pseudogene CYP4Z2P acts as a sub-ceRNET to promote CDK3 expression in ER-positive breast cancer and is a potential therapeutic target for treatment of tamoxifen-resistant breast cancer.
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Lufeng
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Meng
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Chou
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jinhang
authors.initials: J
authors.lastname: Hu
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Zhiting
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xitao18@hotmail.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
mesh_terms: D020413:3' Untranslated Regions; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D000072470:Cytochrome P450 Family 4 / Q000235:genetics*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D011544:Pseudogenes; D012334:RNA, Neoplasm / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D020413:3' Untranslated Regions; D018931:Antineoplastic Agents, Hormonal; D012334:RNA, Neoplasm; D013629:Tamoxifen; C485207:CYP4Z1 protein, human; D000072470:Cytochrome P450 Family 4
keywords: 3′UTR; Breast cancer; CDK3; Pseudogene; Tamoxifen resistance; ceRNA