RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis
RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis
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DOI：
10.1038/nature09495
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发表时间：
2010-11-04
期刊：
影响因子：
64.8
通讯作者：
Dougall, William C.
中科院分区：
文献类型：
--
作者：
Gonzalez-Suarez, Eva;Jacob, Allison P.;Dougall, William C.
RANKL是一种与肿瘤坏死因子相关的分子，通过与其受体RANK(1，2)相互作用，对破骨细胞的形成、功能和存活起着至关重要的作用。RANK和RANKL缺陷小鼠的乳腺在性成熟过程中发育正常，但由于乳腺上皮细胞增殖缺陷和细胞凋亡增加，在妊娠期未能形成小叶肺泡结构。已证明RANKL在小鼠乳腺形态发生过程中对孕酮的主要增殖反应负责(4)，在小鼠模型中，在缺乏严格的激素控制的情况下，操纵以诱导RANK/RANKL通路的激活，观察到不适当的乳腺增殖(5，6)。然而，到目前为止，还没有证据表明RANKL在肿瘤发生中起到了功能作用。在这里，我们发现RANK和RANKL在正常、癌前和肿瘤乳腺上皮细胞中表达，并使用互补的功能获得(小鼠乳腺肿瘤病毒(MMTV)-RANK转基因小鼠)和功能丧失(RANKL的药物抑制)的方法，确定了这一途径在乳腺肿瘤发生中的直接贡献。在多胎或用致癌物质和激素(孕酮)治疗后，观察到MMTV-RANK转基因小鼠加速了癌前病变和增加了乳腺肿瘤的形成。反过来，选择性药物抑制RANKL不仅可以抑制荷尔蒙和致癌物治疗的MMTV-RANK和野生型小鼠的乳腺肿瘤发展，而且还可以抑制MMTV-neu转基因自发肿瘤模型的发展。在RANKL抑制后肿瘤形成的减少之前，癌前病变的减少以及激素和致癌物诱导的乳腺上皮细胞增殖和细胞周期蛋白D1水平的快速和持续减少。综上所述，我们的结果表明，RANKL抑制在肿瘤形成的早期阶段直接作用于激素诱导的乳腺上皮，而孕酮对乳腺癌发病率增加的允许贡献是由于依赖RANKL的乳腺上皮的增殖变化。目前的研究强调了RANKL抑制在治疗增生性乳腺疾病中的潜在作用。
RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK(1,2). Mammary glands of RANK-and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium(3). It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis(4), and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed(5,6). However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone-and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone-and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.