Laboratory of Chromatin Biology & Epigenetics, Center for Integrative Biology (CIBIO), University of Trento, 38123, Trento, Italy.
Fondazione Istituto Nazionale di Genetica Molecolare "Romeo ed Enrica Invernizzi", Via F. Sforza 35, 20122, Milan, Italy.
Nat Commun. 2018 Mar 9;9(1):1024. doi: 10.1038/s41467-018-03264-2.
Breast cancer consists of highly heterogeneous tumors, whose cell of origin and driver oncogenes are difficult to be uniquely defined. Here we report that MYC acts as tumor reprogramming factor in mammary epithelial cells by inducing an alternative epigenetic program, which triggers loss of cell identity and activation of oncogenic pathways. Overexpression of MYC induces transcriptional repression of lineage-specifying transcription factors, causing decommissioning of luminal-specific enhancers. MYC-driven dedifferentiation supports the onset of a stem cell-like state by inducing the activation of de novo enhancers, which drive the transcriptional activation of oncogenic pathways. Furthermore, we demonstrate that the MYC-driven epigenetic reprogramming favors the formation and maintenance of tumor-initiating cells endowed with metastatic capacity. This study supports the notion that MYC-driven tumor initiation relies on cell reprogramming, which is mediated by the activation of MYC-dependent oncogenic enhancers, thus establishing a therapeutic rational for treating basal-like breast cancers.
乳腺癌由高度异质的肿瘤组成，其细胞起源和驱动癌基因难以唯一定义。在这里，我们报告 MYC 通过诱导替代表观遗传程序在乳腺上皮细胞中充当肿瘤重编程因子，从而触发细胞身份丧失和致癌途径激活。MYC 的过表达导致谱系特异性转录因子的转录抑制，导致腔特定增强子的停用。MYC 驱动的去分化通过诱导从头增强子的激活来支持干细胞样状态的出现，从而驱动致癌途径的转录激活。此外，我们证明，由 MYC 驱动的表观遗传重编程有利于形成和维持具有转移能力的肿瘤起始细胞。这项研究支持这样一种观点，即 MYC 驱动的肿瘤起始依赖于细胞重编程，该重编程由 MYC 依赖性致癌增强子的激活介导，从而为治疗基底样乳腺癌提供了治疗合理性。
