Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Clin Invest. 2013 Jan;123(1):150-63. doi: 10.1172/JCI64946. Epub 2012 Dec 17.
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.
晚期乳腺癌转移是由失调的 TGF-β 信号驱动的,但潜在的分子机制尚未完全阐明。我们试图通过使用生物力学顺应性或刚性 3D 器官型培养物来再现肿瘤和转移微环境,并将其与全局 microRNA (miR) 谱分析相结合,以鉴定出 TGF-β 上调的转移性乳腺癌细胞中的 miR。在这里,我们确定 miR-181a 是一种 TGF-β 调节的“转移 mir”,通过促进上皮-间充质转化、迁移和侵袭表型来增强乳腺癌的转移潜力。在机制上,miR-181a 的失活会提高促凋亡分子 Bim 的表达,从而使转移性细胞对无附著生存敏感。沿著这些思路,miR-181a 的表达对于驱动肺微转移的生长和增强小鼠晚期乳腺肿瘤的致死性至关重要。最后,miR-181a 的表达在转移性乳腺癌中显著且选择性地上调,特别是在三阴性乳腺癌中,并且对人类乳腺癌患者的总体生存率具有高度预测性。总的来说,我们的研究结果强烈暗示 miR-181a 作为乳腺癌转移和患者生存的预测性生物标志物,以及转移性乳腺癌的潜在治疗靶点。