Shams Anwar, Binothman Najat, Boudreault Julien, Wang Ni, Shams Fuad, Hamam Dana, Tian Jun, Moamer Alaa, Dai Meiou, Lebrun Jean-Jacques, Ali Suhad
Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Department of Pharmacology, Faculty of Medicine, Taif University, Taif, Saudi Arabia.
Oncogenesis. 2021 Jan 14;10(1):10. doi: 10.1038/s41389-020-00297-5.
Dedifferentiation increased cellular plasticity and stemness are established derivers of tumor heterogeneity, metastasis and therapeutic failure resulting in incurable cancers. Therefore, it is essential to decipher pro/forward-differentiation mechanisms in cancer that may serve as therapeutic targets. We found that interfering with expression of the receptor for the lactogenic hormone prolactin (PRLR) in breast cancer cells representative of the luminal and epithelial breast cancer subtypes (hormone receptor positive (HR+) and HER2-enriched (HER2-E) resulted in loss of their differentiation state, enriched for stem-like cell subpopulations, and increased their tumorigenic capacity in a subtype-specific manner. Loss of PRLR expression in HR+ breast cancer cells caused their dedifferentiation generating a mesenchymal-basal-like phenotype enriched in CD44+ breast cancer stem-like cells (BCSCs) showing high tumorigenic and metastatic capacities and resistance to anti-hormonal therapy. Whereas loss of PRLR expression in HER2-E breast cancer cells resulted in loss of their luminal differentiation yet enriched for epithelial ALDH+ BCSC population showing elevated HER2-driven tumorigenic, multi-organ metastatic spread, and resistance to anti-HER2 therapy. Collectively, this study defines PRLR as a driver of precise luminal and epithelial differentiation limiting cellular plasticity, stemness, and tumorigenesis and emphasizing the function of pro/forward-differentiation pathways as a foundation for the discovery of anti-cancer therapeutic targets.
去分化增加细胞可塑性和干性，是肿瘤异质性、转移和治疗失败导致癌症无法治愈的既定驱动因素。因此，解读癌症中可能作为治疗靶点的促/正向分化机制至关重要。我们发现，干扰代表管腔型和上皮型乳腺癌亚型（激素受体阳性（HR+）和HER2富集型（HER2-E））的乳腺癌细胞中催乳素（PRLR）受体的表达，会导致其分化状态丧失，富集干细胞样细胞亚群，并以亚型特异性方式增加其致瘤能力。HR+乳腺癌细胞中PRLR表达缺失导致其去分化，产生富含CD44+乳腺癌干细胞样细胞（BCSCs）的间充质-基底样表型，这些细胞具有高致瘤和转移能力以及对抗激素治疗的抗性。而HER2-E乳腺癌细胞中PRLR表达缺失导致其管腔分化丧失，但富集上皮ALDH+ BCSC群体，表现出HER2驱动的致瘤性升高、多器官转移扩散以及对抗HER2治疗的抗性。总体而言，本研究将PRLR定义为精确管腔和上皮分化的驱动因素，限制细胞可塑性、干性和肿瘤发生，并强调促/正向分化途径的功能作为发现抗癌治疗靶点的基础。
