title: Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition.
abstract: Stat3 activation has been implicated as an important driver of brain metastasis in breast cancer, but the critical targets of Stat3 in this process are yet to be fully defined. In this study, we identified the lipid raft organizing protein Caveolin-1 (Cav-1) as a critical genetic target of Stat3 in this process. In human breast cancers, we found that activated Stat3 correlated with attenuation of Cav-1 in brain metastases relative to primary tumors. Cav-1 promoter activity and gene expression were increased by overexpressing an activated form of Stat3 but decreased by attenuation of Stat3 activity or expression. We identified putative Stat3-binding elements in the Cav-1 promoter and showed a direct repression of Cav-1 transcription by Stat3. Reciprocally, we showed that strategies to increase or decrease Cav-1 expression were sufficient to attenuate or promote breast cancer cell invasion. Furthermore, increased expression of Cav-1 phenocopied the effects of Stat3 activation in blocking primary tumor growth and abrogating formation of brain metastases. Collectively, our findings provide clinical and mechanistic evidence that Cav-1 is a critical target for suppression by Stat3 in driving invasion and metastasis of breast cancer cells.
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wen-Tai
authors.initials: WT
authors.lastname: Chiu
authors.forename: Hsueh-Te
authors.initials: HT
authors.lastname: Lee
authors.forename: Feng-Ju
authors.initials: FJ
authors.lastname: Huang
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Chou
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Lu
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D051242:Caveolin 1 / Q000096:biosynthesis* / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051242:Caveolin 1; D034741:RNA, Small Interfering; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins