The role of the tumour-suppressor miR-34 family in breast physiology and in mammary stem cells (MaSCs) is largely unknown. Here, we revealed that miR-34 family, and miR-34a in particular, is implicated in mammary epithelium homoeostasis. Expression of miR-34a occurs upon luminal commitment and differentiation and serves to inhibit the expansion of the pool of MaSCs and early progenitor cells, likely in a p53-independent fashion. Mutant mice (miR34-KO) and loss-of-function approaches revealed two separate functions of miR-34a, controlling both proliferation and fate commitment in mammary progenitors by modulating several pathways involved in epithelial cell plasticity and luminal-to-basal conversion. In particular, miR-34a acts as endogenous inhibitor of the Wnt/beta-catenin signalling pathway, targeting up to nine upstream regulators at the same time, thus modulating the expansion of the MaSCs/early progenitor pool. These multiple roles of miR-34a are maintained in a model of human breast cancer, in which chronic expression of miR-34a in triple-negative mesenchymal-like cells (enriched in cancer stem cells-CSCs) could promote a luminal-like differentiation programme, restrict the CSC pool, and inhibit tumour propagation. Hence, activation of miR-34a-dependent programmes could provide a therapeutic opportunity for the subset of breast cancers, which are rich in CSCs and respond poorly to conventional therapies.

中文翻译：

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miR-34a在乳腺和乳腺癌中控制早期祖细胞增殖和定向的双重作用。

肿瘤抑制物miR-34家族在乳腺生理学和乳腺干细胞（MaSCs）中的作用尚不清楚。在这里，我们揭示了miR-34家族，特别是miR-34a，与乳腺上皮的同位性有关。miR-34a的表达发生在管腔定型和分化时，并可能以不依赖p53的方式抑制MaSC和早期祖细胞池的扩增。突变小鼠（miR34-KO）和功能丧失方法揭示了miR-34a的两种独立功能，它们通过调节参与上皮细胞可塑性和管腔至基底转化的几种途径来控制乳腺祖细胞的增殖和命运。特别是，miR-34a充当Wnt /β-catenin信号传导途径的内源性抑制剂，同时定位多达9个上游监管机构，从而调节了MaSC /早期祖先库的扩展。miR-34a的这些多重作用在人类乳腺癌模型中得以维持，其中miR-34a在三阴性间充质样细胞（富含癌干细胞-CSC）中的慢性表达可以促进管腔样分化程序，限制CSC库并抑制肿瘤的扩散。因此，miR-34a依赖程序的激活可以为乳腺癌的子集提供治疗机会，这些子集富含CSCs，并且对常规疗法的反应较差。其中miR-34a在三阴性间充质样细胞（富含癌干细胞-CSC）中的慢性表达可以促进管腔样分化程序，限制CSC库并抑制肿瘤扩散。因此，miR-34a依赖程序的激活可以为乳腺癌的子集提供治疗机会，这些子集富含CSCs，并且对常规疗法的反应较差。其中miR-34a在三阴性间充质样细胞（富含癌干细胞-CSC）中的慢性表达可促进管腔样分化程序，限制CSC池，并抑制肿瘤扩散。因此，miR-34a依赖程序的激活可以为乳腺癌的子集提供治疗机会，这些子集富含CSCs，并且对常规疗法的反应较差。