Stem Cells. 2013 Sep;31(9):1954-65. doi: 10.1002/stem.1454.
Receptor Activator of NF-kappa B (RANK) pathway controls mammary gland development in mice but its role in mammary stem cell fate remains undefined. We show that constitutive RANK signaling expands luminal and basal mammary compartments including mammary stem and luminal progenitor cell pools and interferes with the generation of CD61+ and Sca1+ luminal cells and Elf5 expression. Impaired mammary cell commitment upon RANK overexpression leads to the accumulation of progenitors including K14+K8+ bipotent cells and the formation of heterogeneous tumors containing hyperplastic basal, luminal, and progenitor cells. RANK expression increases in wild-type mammary epithelia with age and parity, and spontaneous preneoplastic lesions express RANK and accumulate K14+K8+ cells. In human breast tumors, high RANK expression levels are also associated with altered mammary differentiation. These results suggest that increased RANK signaling interferes with mammary cell commitment, contributing to breast carcinogenesis.
核因子-κB（NF-κB）受体激活物（RANK）通路控制着小鼠乳腺的发育，但它在乳腺干细胞命运中的作用仍未确定。我们发现，组成性 RANK 信号会扩大乳腺腔和基底细胞区室，包括乳腺干细胞和腔前体细胞池，并干扰 CD61+和 Sca1+腔细胞和 Elf5 表达的产生。RANK 过表达导致乳腺细胞分化受阻，从而导致包括 K14+K8+双能细胞在内的祖细胞积累，并形成含有增生的基底、腔和祖细胞的异质性肿瘤。RANK 在野生型乳腺上皮中的表达随着年龄和胎次的增加而增加，自发的前瘤病变表达 RANK 并积累 K14+K8+细胞。在人类乳腺癌中，高 RANK 表达水平也与乳腺分化改变有关。这些结果表明，增加的 RANK 信号干扰了乳腺细胞的分化，促进了乳腺癌的发生。
