Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Institut Curie, 75248 Paris Cedex 05, France.
Cell Stem Cell. 2014 Dec 4;15(6):762-74. doi: 10.1016/j.stem.2014.10.001. Epub 2014 Oct 16.
Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer.
间充质干细胞（MSCs）是参与乳腺肿瘤基质形成并促进转移的祖细胞。尽管人们对它们在乳腺恶性肿瘤中的作用有了更多的了解，但乳腺癌细胞（BCCs）对 MSC 影响的潜在分子反应仍不完全清楚。在这里，我们表明 MSCs 导致 microRNAs 的异常表达，microRNA-199a 起主导作用，为 BCCs 提供了增强的癌症干细胞（CSC）特性。我们证明，这种 MSC 失调的 microRNAs 构成了一个网络，该网络集中并抑制叉头框转录因子 FOXP2 的表达，FOXP2 与言语和语言发展密切相关。在 BCCs 中敲低 FOXP2 足以促进 CSC 的增殖、肿瘤起始和转移。重要的是，升高的 microRNA-199a 和降低的 FOXP2 表达水平是恶性临床乳腺癌的显著特征，并与不良预后显著相关。我们的研究结果确定了癌症进展的分子决定因素，这些决定因素可能对乳腺癌的预后和治疗具有潜在的应用价值。
