title: miR-21 induces myofibroblast differentiation and promotes the malignant progression of breast phyllodes tumors.
abstract: Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and stromal cell-derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to α-SMA-positive myofibroblasts. More importantly, α-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of α-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21.
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Chang
authors: C
authors: Gong
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Yan
authors: Y
authors: Nie
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Shaohua
authors: S
authors: Qu
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Jian-You
authors: JY
authors: Liao
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Xiuying
authors: X
authors: Cui
authors: Department of Oncology, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Herui
authors: H
authors: Yao
authors: Department of Pathology, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Yunjie
authors: Y
authors: Zeng
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
authors: Fengxi
authors: F
authors: Su
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. victorlq@hotmail.com songew@mail.sysu.edu.cn.
authors: Erwei
authors: E
authors: Song
authors: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China. victorlq@hotmail.com songew@mail.sysu.edu.cn.
authors: Qiang
authors: Q
authors: Liu
mesh_terms: D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D005260:Female; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D058628:Myofibroblasts / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D003557:Phyllodes Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology; D014162:Transfection; D015854:Up-Regulation
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human