title: TGF-β upregulates miR-181a expression to promote breast cancer metastasis.
abstract: Late-stage breast cancer metastasis is driven by dysregulated TGF-β signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic microenvironments via the use of biomechanically compliant or rigid 3D organotypic cultures and combined them with global microRNA (miR) profiling analyses to identify miRs that were upregulated in metastatic breast cancer cells by TGF-β. Here we establish miR-181a as a TGF-β-regulated "metastamir" that enhanced the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory, and invasive phenotypes. Mechanistically, inactivation of miR-181a elevated the expression of the proapoptotic molecule Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a expression was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients. Collectively, our findings strongly implicate miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, and consequently, as a potential therapeutic target in metastatic breast cancer.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Taylor
authors.forename: Khalid
authors.initials: K
authors.lastname: Sossey-Alaoui
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Thompson
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C540193:MIrn181 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D016212:Transforming Growth Factor beta