Molecular Biotechnology Center (MBC), University of Torino, Via Nizza, 52, 10126 Torino, Italy.
FASEB J. 2013 Mar;27(3):1223-35. doi: 10.1096/fj.12-214692. Epub 2012 Dec 11.
Breast cancer is often fatal during its metastatic dissemination. To unravel the role of microRNAs (miRs) during malignancy, we analyzed miR expression in 77 primary breast carcinomas and identified 16 relapse-associated miRs that correlate with survival and/or distinguish tumor subtypes in different datasets. Among them, miR-148b, down-regulated in aggressive breast tumors, was found to be a major coordinator of malignancy. In fact, it is able to oppose various steps of tumor progression when overexpressed in cell lines by influencing invasion, survival to anoikis, extravasation, lung metastasis formation, and chemotherapy response. miR-148b controls malignancy by coordinating a novel pathway involving over 130 genes and, in particular, it directly targets players of the integrin signaling, such as ITGA5, ROCK1, PIK3CA/p110α, and NRAS, as well as CSF1, a growth factor for stroma cells. Our findings reveal the importance of the identified 16 miRs for disease outcome predictions and suggest a critical role for miR-148b in the control of breast cancer progression.
乳腺癌在转移扩散时往往是致命的。为了揭示 microRNAs（miRs）在恶性肿瘤中的作用，我们分析了 77 例原发性乳腺癌中的 miR 表达情况，并在不同的数据集确定了 16 个与生存相关且能区分肿瘤亚型的复发相关 miR。其中，在侵袭性乳腺癌中下调的 miR-148b 被发现是恶性肿瘤的主要协调因子。事实上，当它在细胞系中过表达时，通过影响侵袭、抗凋亡、血管外渗、肺转移形成和化疗反应，它能够对抗肿瘤进展的各个步骤。miR-148b 通过协调涉及超过 130 个基因的新途径来控制恶性肿瘤，特别是它直接靶向整合素信号的参与者，如 ITGA5、ROCK1、PIK3CA/p110α 和 NRAS，以及基质细胞的生长因子 CSF1。我们的研究结果揭示了鉴定出的 16 个 miRs 对疾病预后预测的重要性，并表明 miR-148b 在控制乳腺癌进展中起着关键作用。
