Paracrine activation of cells contained in the tumor microenvironment promotes tumor progression and metastasis. In breast cancer, malignant cells recruit and educate macrophages into a M2 tumor-promoting phenotype that supports the metastatic spread of cancer cells. Here, we show that miR-149 functions as a metastasis-suppressing microRNA in breast cancer cells by limiting colony-stimulating factor-1 (CSF1)-dependent recruitment and M2 polarization of macrophages. In lymph node-positive, triple-negative breast cancer (TNBC) tissues, low miR-149 expression correlated with macrophage infiltration and reduced patient survival. By directly targeting CSF1, miR-149 expression in TNBC cell lines (MDA-MB-231 and BT-549) inhibited the recruitment of human monocytic THP-1 cells and primary human macrophages. Furthermore, in macrophages cocultured with MDA-MB-231 cells expressing miR-149, epidermal growth factor (EGF) and amphiregulin expression levels were strongly reduced, resulting in reduced EGF receptor activation in the cancer cells. In vivo, lung metastases developing from orthotopic MDA-MB-231 tumors were reduced by 75% by miR-149 expression, and this was associated with impaired M2 macrophage infiltration of the primary tumors. These data suggest that miR-149 downregulation functionally contributes to breast tumor progression by recruiting macrophages to the tumor and facilitating CSF1 and EGF receptor cross-talk between cancer cells and macrophages. SIGNIFICANCE: These findings contribute to the understanding of tumor-stroma interactions by showing that miR-149 downregulation in TNBC enhances reciprocal growth factor signaling between macrophages and cancer cells, which promotes tumor progression and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpg.

中文翻译：

---

miR-149通过阻断旁分泌与巨噬细胞的相互作用来抑制乳腺癌的转移。

肿瘤微环境中所含细胞的旁分泌激活促进了肿瘤的进展和转移。在乳腺癌中，恶性细胞募集并教育巨噬细胞成为支持癌细胞转移扩散的M2促进肿瘤表型。在这里，我们显示miR-149通过限制集落刺激因子1（CSF1）依赖的募集和巨噬细胞的M2极化，在乳腺癌细胞中充当转移抑制的microRNA。在淋巴结阳性，三阴性乳腺癌（TNBC）组织中，低miR-149表达与巨噬细胞浸润和患者生存率降低相关。通过直接靶向CSF1，TNR细胞系（MDA-MB-231和BT-549）中的miR-149表达抑制了人单核THP-1细胞和原代人巨噬细胞的募集。此外，在与表达miR-149的MDA-MB-231细胞共培养的巨噬细胞中，表皮生长因子（EGF）和双调蛋白的表达水平显着降低，导致癌细胞中EGF受体的激活减少。在体内，miR-149表达使原位MDA-MB-231肿瘤发生的肺转移减少了75％，这与原发肿瘤的M2巨噬细胞浸润受损有关。这些数据表明，miR-149的下调通过在肿瘤中募集巨噬细胞并促进癌细胞与巨噬细胞之间的CSF1和EGF受体串扰而在功能上有助于乳腺肿瘤进展。意义：这些发现通过显示TNBC中的miR-149下调增强了巨噬细胞和癌细胞之间的相互生长因子信号传导，从而促进了肿瘤进展和转移，有助于理解肿瘤-基质相互作用。图形摘要：http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpg。