RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis

被引:448
作者
Gonzalez-Suarez, Eva [1 ]
Jacob, Allison P. [1 ]
Jones, Jon [1 ]
Miller, Robert [1 ]
Roudier-Meyer, Martine P. [2 ]
Erwert, Ryan [1 ]
Pinkas, Jan [3 ]
Branstetter, Dan [2 ]
Dougall, William C. [1 ]
机构
[1] Amgen Inc, Dept Hematol Oncol Res, Seattle, WA 98119 USA
[2] Amgen Inc, Dept Pathol, Seattle, WA 98119 USA
[3] Amgen Inc, Dept Hematol Oncol Res, Cambridge, MA 02139 USA
关键词
HORMONE REPLACEMENT THERAPY; HUMAN BREAST-TUMORS; GLAND DEVELOPMENT; TRANSGENIC MICE; MEDROXYPROGESTERONE ACETATE; OSTEOCLAST DIFFERENTIATION; OSTEOPROTEGERIN-LIGAND; CELL FUNCTION; RECEPTOR; EXPRESSION;
D O I
10.1038/nature09495
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页码:103 / +
页数:7
相关论文
共 28 条
[1]   Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene [J].
Aldaz, CM ;
Liao, QY ;
LaBate, M ;
Johnston, DA .
CARCINOGENESIS, 1996, 17 (09) :2069-2072
[2]   A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function [J].
Anderson, DM ;
Maraskovsky, E ;
Billingsley, WL ;
Dougall, WC ;
Tometsko, ME ;
Roux, ER ;
Teepe, MC ;
DuBose, RF ;
Cosman, D ;
Galibert, L .
NATURE, 1997, 390 (6656) :175-179
[3]   Control of mammary stem cell function by steroid hormone signalling [J].
Asselin-Labat, Marie-Liesse ;
Vaillant, Francois ;
Sheridan, Julie M. ;
Pal, Bhupinder ;
Wu, Di ;
Simpson, Evan R. ;
Yasuda, Hisataka ;
Smyth, Gordon K. ;
Martin, T. John ;
Lindeman, Geoffrey J. ;
Visvader, Jane E. .
NATURE, 2010, 465 (7299) :798-802
[4]  
Aupperlee Mark, 2005, Breast Dis, V24, P37
[5]   Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland [J].
Beleut, Manfred ;
Rajaram, Renuga Devi ;
Caikovski, Marian ;
Ayyanan, Ayyakkannu ;
Germano, Davide ;
Choi, Yongwon ;
Schneider, Pascal ;
Brisken, Cathrin .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (07) :2989-2994
[6]   A paracrine role for the epithelial progesterone receptor in mammary gland development [J].
Brisken, C ;
Park, S ;
Vass, T ;
Lydon, JP ;
O'Malley, BW ;
Weinberg, RA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (09) :5076-5081
[7]   IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development [J].
Cao, YX ;
Bonizzi, G ;
Seagroves, TN ;
Greten, FR ;
Johnson, R ;
Schmidt, EV ;
Karin, M .
CELL, 2001, 107 (06) :763-775
[8]   The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting [J].
Cardiff, RD ;
Anver, MR ;
Gusterson, BA ;
Hennighausen, L ;
Jensen, RA ;
Merino, MJ ;
Rehm, S ;
Russo, J ;
Tavassoli, FA ;
Wakefield, LM ;
Ward, JM ;
Green, JE .
ONCOGENE, 2000, 19 (08) :968-988
[9]   Influence of estrogen plus progestin on breast, cancer and mammography in healthy postmenopausal women - The Women's Health Initiative Randomized trial [J].
Chlebowski, RT ;
Hendrix, SL ;
Langer, RD ;
Stefanick, ML ;
Gass, M ;
Lane, D ;
Rodabough, RJ ;
Gilligan, MA ;
Cyr, MG ;
Thomson, CA ;
Khandekar, J ;
Petrovitch, H ;
McTiernan, A .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2003, 289 (24) :3243-3253
[10]   RANK is essential for osteoclast and lymph node development [J].
Dougall, WC ;
Glaccum, M ;
Charrier, K ;
Rohrbach, K ;
Brasel, K ;
De Smedt, T ;
Daro, E ;
Smith, J ;
Tometsko, ME ;
Maliszewski, CR ;
Armstrong, A ;
Shen, V ;
Bain, S ;
Cosman, D ;
Anderson, D ;
Morrissey, PJ ;
Peschon, JJ ;
Schuh, J .
GENES & DEVELOPMENT, 1999, 13 (18) :2412-2424