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.

去分化增加的细胞可塑性和干性是肿瘤异质性、转移和导致无法治愈的癌症的治疗失败的既定推导因素。因此，有必要破译癌症中可作为治疗靶点的促/正向分化机制。我们发现，干扰代表管腔和上皮乳腺癌亚型（激素受体阳性 (HR+) 和 HER2 富集 (HER2-E)）的乳腺癌细胞中催乳激素催乳素 (PRLR) 受体的表达会导致它们的分化状态，富含干细胞样细胞亚群，并以亚型特异性方式增加它们的致瘤能力。HR+ 乳腺癌细胞中 PRLR 表达的缺失导致它们的去分化产生富含 CD44+ 乳腺癌干细胞样细胞 (BCSC) 的间充质-基底样表型，显示出高致瘤性和转移能力以及抗激素治疗的抗性。而 HER2-E 乳腺癌细胞中 PRLR 表达的缺失导致其管腔分化缺失，但上皮 ALDH+ BCSC 群体富集，显示 HER2 驱动的致瘤性、多器官转移扩散和抗 HER2 治疗耐药性升高。总的来说，这项研究将 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，并强调前/正向分化途径的功能作为发现抗癌治疗靶点的基础。