title: Yap1 promotes the survival and self-renewal of breast tumor initiating cells via inhibiting Smad3 signaling.
abstract: Tumor initiating cells (TICs) serve as the root of tumor growth. After identifying TICs in spontaneous breast tumors of the MMTV-Wnt1 mouse model, we confirmed the specific expression and activation of Yes-associated protein 1 (Yap1) within TICs. To investigate the role of Yap1 in the self-renewal of breast TICs and the underlying mechanism, we sorted CD49fhighEpCAMlow cells as breast TICs. Active Yap1 with ectopic expression in breast TICs promoted their colony formation in vitro (p< 0.01) and self-renewal in vivo (p< 0.01), and led to a 4-fold increase in TIC frequency (p< 0.05).A conditional knock-out mouse was reconstructed to generate Yap1 knock-out breast tumors. The loss of Yap1 led to a dramatic growth disadvantage of breast TICs in vitro (p< 0.01) and in vivo (p< 0.01), and it also led to an over 200-fold decrease in TIC frequency (p< 0.01). The expression of active Yap1 was negatively correlated with that of phosphorylated Smad3 (p-Smad3).Transforming growth factor β (TGF-β) served as a strong enhancer of Smad3 and an inhibitor of clonogenesis of TICs. The presence of SIS3, a specific inhibitor of Smad3, could rescue the TGF-β -induced growth inhibition and reverse the Smad3 inhibition by Yap1. Analysis of a database containing 2,072 human breast cancer samples showed that higher expressions of Yap1 correlated with a poorer outcome of a 15-year survival rate and median overall survival (mOS)in patients, especially in those with basal breast tumors without estrogen receptor 1 (ER) expression. The findings indicate that active Yap1 promotes the self-renewal of breast TICs by inhibiting Smad3 signaling.
authors.affiliation: Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.|Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Sun
authors.affiliation: Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China.
authors.forename: Xie-Wan
authors.initials: XW
authors.lastname: Chen
authors.affiliation: Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China.
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Second Affiliated Hospital of Third Military Medical University, Chongqing, P.R. China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Diehn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051900:Smad3 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics; D000091102:YAP-Signaling Proteins
chemical_list: C508504:6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007546:Isoquinolines; D010750:Phosphoproteins; D011725:Pyridines; D011758:Pyrroles; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse
keywords: Smad3; Yap1; breast cancer; self-renewal; tumor initialing cells