Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancer.
Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancer.
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DOI：
10.1038/s41388-018-0445-3
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发表时间：
2019-01
期刊：
影响因子：
8
通讯作者：
Nicassio F
中科院分区：
文献类型：
--
作者：
Bonetti P;Climent M;Panebianco F;Tordonato C;Santoro A;Marzi MJ;Pelicci PG;Ventura A;Nicassio F
肿瘤抑制因子 miR-34 家族在乳腺生理学和乳腺干细胞 (MaSC) 中的作用很大程度上未知。在这里，我们揭示了 miR-34 家族，特别是 miR-34a，与乳腺上皮稳态有关。 miR-34a 的表达发生在管腔定型和分化时，并可能以不依赖于 p53 的方式抑制 MaSC 和早期祖细胞库的扩张。突变小鼠 (miR34-KO) 和功能丧失方法揭示了 miR-34a 的两个独立功能，通过调节涉及上皮细胞可塑性和管腔到基底细胞转化的多个途径来控制乳腺祖细胞的增殖和命运决定。特别是，miR-34a 作为 Wnt/β-catenin 信号通路的内源性抑制剂，同时针对多达 9 个上游调节因子，从而调节 MaSC/早期祖细胞池的扩张。 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（富含癌症干细胞 - CSC）中的长期表达可以促进管腔样分化程序，限制 CSC 池并抑制肿瘤增殖。因此，miR-34a依赖性程序的激活可以为乳腺癌亚群提供治疗机会，这些乳腺癌富含CSC并且对传统疗法反应不佳。
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.
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45.3
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