期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 1, 页码 150-163出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI64946
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资金
- NIH [CA129359]
- Komen Foundation [BCTR0706967]
- University of Colorado Cancer Center Breast Program Gift Fund
- Case Comprehensive Cancer Center [P30 CA043703]
- Department of Defense [BC093128]
- NATIONAL CANCER INSTITUTE [P30CA043703, K07CA136758, R01CA129359] Funding Source: NIH RePORTER
Late-stage breast cancer metastasis is driven by dysregulated TGF-beta signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic micro-environments 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-beta. Here we establish miR-18 la as a TGF-beta-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.
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