title: Metastatic heterogeneity of breast cancer cells is associated with expression of a heterogeneous TGFβ-activating miR424-503 gene cluster.
abstract: TGFβ signaling is known to drive metastasis in human cancer. Under physiologic conditions, the level of TGFβ activity is tightly controlled by a regulatory network involving multiple negative regulators. At metastasis, however, these inhibitory mechanisms are usually overridden so that oncogenic TGFβ signaling can be overactivated and sustained. To better understand how the TGFβ inhibitors are suppressed in metastatic breast cancer cells, we compared miRNA expression profiles between breast cancers with or without metastasis and found that the miR424-503 cluster was markedly overexpressed in metastatic breast cancer. Mechanistic studies revealed that miR424 and miR503 simultaneously suppressed Smad7 and Smurf2, two key inhibitory factors of TGFβ signaling, leading to enhanced TGFβ signaling and metastatic capability of breast cancer cells. Moreover, antagonizing miR424-503 in breast cancer cells suppressed metastasis in vivo and increased overall host survival. Interestingly, our study also found that heterogeneous expression of the miR424-503 cluster contributed to the heterogeneity of TGFβ activity levels in, and metastatic potential of, breast cancer cell subsets. Overall, our findings demonstrate a novel mechanism, mediated by elevated expression of the miR424-503 cluster, underlying TGFβ activation and metastasis of human breast cancer.
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ying
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China.
authors.forename: Han
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China. Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Chinese Ministry of Education, Guangzhou, Guangdong, China. limf@mail.sysu.edu.cn.
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D018740:Genetic Heterogeneity; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D051906:Smad7 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C554214:MIRN424 microrna, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases