细胞状态控制对于正常组织发育和癌细胞模仿干细胞/祖细胞状态至关重要，有助于肿瘤异质性、治疗抵抗和进展。在这里，我们证明细胞表面糖蛋白 Mcam 维持致瘤性管腔祖细胞 (LP) 样上皮细胞状态，从而导致基底样乳腺癌。在 Py230 小鼠乳腺癌模型中，Mcam 敲低 (KD) 通过解除 Ck2/Stat3 轴的调节而破坏 LP 状态的稳定，导致向肺泡和基底状态的转变、雌激素敏感亚群的丧失以及对他莫昔芬效应的耐药性逆转通过 Ck2 和 Stat3 抑制剂。在体内，Mcam KD 阻断了 Basal 样肿瘤和 Sox10 Krt14 细胞的生成。在人类肿瘤中，MCAM 缺失很大程度上排除了 Basal 样亚型，而是与增殖性 Luminal 亚型相关，包括通常具有内分泌抵抗性的 Luminal B 癌。这项研究对于开发针对 MCAM、CK2 和 STAT3 的疗法及其可能有效的背景具有重要意义。© 2024。作者。

Cell state control is crucial for normal tissue development and cancer cell mimicry of stem/progenitor states, contributing to tumor heterogeneity, therapy resistance, and progression. Here, we demonstrate that the cell surface glycoprotein Mcam maintains the tumorigenic luminal progenitor (LP)-like epithelial cell state, leading to Basal-like mammary cancers. In the Py230 mouse mammary carcinoma model, Mcam knockdown (KD) destabilized the LP state by deregulating the Ck2/Stat3 axis, causing a switch to alveolar and basal states, loss of an estrogen-sensing subpopulation, and resistance to tamoxifen-an effect reversed by Ck2 and Stat3 inhibitors. In vivo, Mcam KD blocked generation of Basal-like tumors and Sox10+Krt14+ cells. In human tumors, MCAM loss was largely exclusive of the Basal-like subtype, linked instead to proliferative Luminal subtypes, including often endocrine-resistant Luminal B cancers. This study has implications for developing therapies targeting MCAM, CK2, and STAT3 and their likely effective contexts.© 2024. The Author(s).