González-Suárez Eva, Sanz-Moreno Adrián
Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, IDIBELL, Barcelona, Spain.
FEBS J. 2016 Jun;283(11):2018-33. doi: 10.1111/febs.13645. Epub 2016 Jan 28.
The RANK signaling pathway has emerged as a new target in breast cancer as receptor activator of nuclear factor κB ligand (RANKL) and its receptor RANK mediate the pro-tumorigenic role of progesterone in the mammary gland. Thousands of cancer patients worldwide are already taking RANKL inhibitors for the management of bone metastasis, given the relevance of this pathway in osteoclastogenesis and bone resorption. RANK signaling also has multiple divergent effects in immunity and inflammation, both in the generation of active immune responses and in the induction of tolerance: it is required for lymph node organogenesis, thymic medullary epithelial development and self-tolerance, and regulates activation of several immune cells and inflammatory processes. The RANK pathway interferes with mammary epithelial differentiation and mediates the major proliferative response of mammary epithelium to progesterone and progesterone-driven expansion of mammary stem cells; it also controls hair follicle and epidermal stem cell homeostasis, pointing to RANK as a key regulator of epithelial stemness. Here we revisit the main functions of RANK signaling in bone remodeling, immune cells and epithelial differentiation. We also discuss the mechanistic evidence that supports its pleiotropic effects on cancer: from bone metastasis to immune and cancer-cell-dependent effects.
核因子κB受体活化因子（RANK）信号通路已成为乳腺癌的一个新靶点，因为核因子κB配体（RANKL）及其受体RANK介导了孕酮在乳腺中的促肿瘤作用。鉴于该通路在破骨细胞生成和骨吸收中的相关性，全球已有数千名癌症患者正在服用RANKL抑制剂来治疗骨转移。RANK信号在免疫和炎症方面也有多种不同的作用，包括在活跃免疫反应的产生和耐受性的诱导方面：它是淋巴结器官发生、胸腺髓质上皮发育和自身耐受性所必需的，并且调节几种免疫细胞的活化和炎症过程。RANK通路干扰乳腺上皮分化，并介导乳腺上皮对孕酮以及孕酮驱动的乳腺干细胞扩增的主要增殖反应；它还控制毛囊和表皮干细胞的稳态，表明RANK是上皮干性的关键调节因子。在这里，我们重新审视RANK信号在骨重塑、免疫细胞和上皮分化中的主要功能。我们还讨论了支持其对癌症具有多效性作用的机制证据：从骨转移到免疫和癌细胞依赖性效应。
