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MicroRNA-200c restoration reveals a cytokine profile to enhance M1 macrophage polarization in breast cancer
npj Breast Cancer ( IF 5.9 ) Pub Date : 2021-05-27 , DOI: 10.1038/s41523-021-00273-1
Michelle M. Williams , Jessica L. Christenson , Kathleen I. O’Neill , Sabrina A. Hafeez , Claire L. Ihle , Nicole S. Spoelstra , Jill E. Slansky , Jennifer K. Richer

Many immune suppressive mechanisms utilized by triple negative breast cancer (TNBC) are regulated by oncogenic epithelial-to-mesenchymal transition (EMT). How TNBC EMT impacts innate immune cells is not fully understood. To determine how TNBC suppresses antitumor macrophages, we used microRNA-200c (miR-200c), a powerful repressor of EMT, to drive mesenchymal-like mouse mammary carcinoma and human TNBC cells toward a more epithelial state. MiR-200c restoration significantly decreased growth of mouse mammary carcinoma Met-1 cells in culture and in vivo. Cytokine profiling of Met-1 and human BT549 cells revealed that miR-200c upregulated cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), promoted M1 antitumor macrophage polarization. Cytokines upregulated by miR-200c correlated with an epithelial gene signature and M1 macrophage polarization in BC patients and predicted a more favorable overall survival for TNBC patients. Our findings demonstrate that immunogenic cytokines (e.g., GM-CSF) are suppressed in aggressive TNBC, warranting further investigation of cytokine-based therapies to limit disease recurrence.



中文翻译:

MicroRNA-200c修复揭示了一种细胞因子谱,可增强乳腺癌中M1巨噬细胞的极化

三阴性乳腺癌(TNBC)利用的许多免疫抑制机制受致癌性上皮-间质转化(EMT)的调节。TNBC EMT如何影响先天免疫细胞尚未完全了解。为了确定TNBC如何抑制抗肿瘤巨噬细胞,我们使用了强大的EMT阻遏物microRNA-200c(miR-200c)来驱动间充质样小鼠乳腺癌和人TNBC细胞趋向上皮状态。MiR-200c的恢复显着降低了小鼠乳腺癌Met-1细胞在培养物中和体内的生长。Met-1和人BT549细胞的细胞因子分析表明,miR-200c上调了细胞因子,例如粒细胞巨噬细胞集落刺激因子(GM-CSF),促进了M1抗肿瘤巨噬细胞极化。miR-200c上调的细胞因子与BC患者的上皮基因特征和M1巨噬细胞极化有关,并预测TNBC患者的总体生存期更为有利。我们的发现表明,在侵袭性TNBC中免疫原性细胞因子(例如GM-CSF)被抑制,因此有必要进一步研究基于细胞因子的疗法以限制疾病的复发。

更新日期:2021-05-27
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