Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer.
Breast cancer stem-like cells (BCSC) have been implicated in tumor growth, metastasis, drug resistance, and relapse but druggable targets in appropriate subsets of this cell population have yet to be identified. Here we identify a fundamental role for the prolyl isomerase Pin1 in driving BCSC expansion, invasiveness, and tumorigenicity, defining it as a key target of miR200c, which is known to be a critical regulator in BCSC. Pin1 overexpression expanded the growth and tumorigenicity of BCSC and triggered epithelial-mesenchymal transition. Conversely, genetic or pharmacological inhibition of Pin1 reduced the abundance and self-renewal activity of BCSC. Moreover, moderate overexpression of miR200c-resistant Pin1 rescued the BCSC defect in miR200c-expressing cells. Genetic deletion of Pin1 also decreased the abundance and repopulating capability of normal mouse mammary stem cells. In human cells, freshly isolated from reduction mammoplasty tissues, Pin1 overexpression endowed BCSC traits to normal breast epithelial cells, expanding both luminal and basal/myoepithelial lineages in these cells. In contrast, Pin1 silencing in primary breast cancer cells freshly isolated from clinical samples inhibited the expansion, self-renewal activity, and tumorigenesis of BCSC in vitro and in vivo. Overall, our work demonstrated that Pin1 is a pivotal regulator acting downstream of miR200c to drive BCSC and breast tumorigenicity, highlighting a new therapeutic target to eradicate BCSC.
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Man-Li
ML
Luo
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou; and.
Chang
C
Gong
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Chun-Hau
CH
Chen
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Daniel Y
DY
Lee
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Hai
H
Hu
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Pengyu
P
Huang
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Yandan
Y
Yao
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts;
Wenjun
W
Guo
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts;
Ferenc
F
Reinhardt
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Gerburg
G
Wulf
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston;
Judy
J
Lieberman
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center;
Xiao Zhen
XZ
Zhou
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou; and.
Erwei
E
Song
Authors' Affiliations: Department of Medicine, Beth Israel Deaconess Medical Center; Institute for Translational Medicine, Fujian Medical University, Fuzhou, China klu@bidmc.harvard.edu.
Kun Ping
KP
Lu
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology*; D019696:Peptidylprolyl Isomerase / Q000096:biosynthesis / Q000235:genetics*; D010618:Phenanthrolines / Q000494:pharmacology; D034622:RNA Interference; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D035683:MicroRNAs; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010618:Phenanthrolines; C552250:diethyl-1,3,6,8-tetrahydro-1,3,6,8-tetraoxobenzo(lmn)(3,8)phenanthroline-2,7-diacetate; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse