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RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis

机译：RANK配体介导孕激素诱导的乳腺上皮增殖和致癌作用

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摘要

RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. 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. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis 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. 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 multi-parity 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 Dl 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.
机译：RANK配体（RANKL）是与TNF相关的分子，通过与破骨细胞受体RANK的相互作用，对破骨细胞的形成，功能和存活至关重要。 RANK和RANKL缺陷型小鼠的乳腺在性成熟过程中正常发育，但由于乳腺上皮的增殖缺陷和凋亡增加，在怀孕期间未能形成小肺泡结构。研究表明，RANKL负责小鼠乳腺上皮形态发生过程中小鼠乳腺上皮对孕酮的主要增殖反应，在小鼠模型中，在没有严格的激素控制的情况下，操纵该模型以诱导RANK / RANKL途径活化，不适当的乳腺增殖是观测到的。但是，到目前为止，尚无证据表明RANKL对肿瘤发生有功能性贡献。在这里，我们显示RANK和RANKL在正常，恶变前和赘生性乳腺上皮中表达，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（药理学抑制） RANKL）方法定义了该途径在乳腺肿瘤发生中的直接贡献。 MMTV-RANK转基因小鼠经过多胎奇偶校验或接受致癌物和激素（孕酮）治疗后，观察到加速的前肾病和乳腺肿瘤形成增加。相应地，RANKL的选择性药理抑制作用不仅在激素和致癌物治疗的MMTV-RANK和野生型小鼠中，而且在MMTV-neu转基因自发性肿瘤模型中，都减弱了乳腺肿瘤的发展。 RANKL抑制后肿瘤发生的减少先于neoplasias的减少以及激素和致癌物诱导的乳腺上皮细胞增殖和cyclin D1水平的持续快速减少。总的来说，我们的结果表明，RANKL抑制在肿瘤发生的早期直接作用于激素诱导的乳腺上皮，而孕激素对增加的乳癌发生率的允许作用是由于乳腺上皮中RANKL依赖性的增殖变化所致。当前的研究强调了RANKL抑制在乳腺增生疾病的治疗中的潜在作用。

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  • 来源
    《Nature》 |2010年第7320期|p.103-107|共5页
  • 作者

    Eva Gonzalez-Suarez; Allison P. Jacob; Jon Jones; Robert Miller; Martine P. Roudier-Meyer; Ryan Erwert; Jan Pinkas; Dan Branstetter; William C. Dougall;

  • 作者单位

    Department of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research, 08907-L;

    rnDepartment of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA;

    rnDepartment of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA;

    rnDepartment of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA;

    rnDepartment of Pathology, Amgen Inc, Seattle, Washington 98119, USA;

    rnDepartment of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA;

    rnDepartment of Hematology/ Oncology Research, Amgen Inc, Cambridge, Massachusetts 02139, USA Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research, 08907-L;

    rnDepartment of Pathology, Amgen Inc, Seattle, Washington 98119, USA;

    rnDepartment of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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