Universität zu Köln

Schramek, Daniel ORCID: 0000-0001-9977-2104, Leibbrandt, Andreas, Sigl, Verena, Kenner, Lukas ORCID: 0000-0003-2184-1338, Pospisilik, John A., Lee, Heather J., Hanada, Reiko, Joshi, Purna A., Aliprantis, Antonios, Glimcher, Laurie, Pasparakis, Manolis ORCID: 0000-0002-9870-0966, Khokha, Rama, Ormandy, Christopher J., Widschwendter, Martin ORCID: 0000-0002-7778-8380, Schett, Georg and Penninger, Josef M. (2010). Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature, 468 (7320). S. 98 - 105. BERLIN: NATURE RESEARCH. ISSN 1476-4687

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Abstract

Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe(1). The Women's Health Initiative and the Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer(2,3). In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-kappa B ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49f(hi) stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schramek, Daniel UNSPECIFIED orcid.org/0000-0001-9977-2104 UNSPECIFIED Leibbrandt, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Sigl, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Kenner, Lukas UNSPECIFIED orcid.org/0000-0003-2184-1338 UNSPECIFIED Pospisilik, John A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Heather J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hanada, Reiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Joshi, Purna A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aliprantis, Antonios UNSPECIFIED UNSPECIFIED UNSPECIFIED Glimcher, Laurie UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED Khokha, Rama UNSPECIFIED UNSPECIFIED UNSPECIFIED Ormandy, Christopher J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Widschwendter, Martin UNSPECIFIED orcid.org/0000-0002-7778-8380 UNSPECIFIED Schett, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Penninger, Josef M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-492693
DOI:	10.1038/nature09387
Journal or Publication Title:	Nature
Volume:	468
Number:	7320
Page Range:	S. 98 - 105
Date:	2010
Publisher:	NATURE RESEARCH
Place of Publication:	BERLIN
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HORMONE-REPLACEMENT THERAPY; ESTROGEN-PLUS-PROGESTIN; STEM-CELL; POSTMENOPAUSAL WOMEN; EPITHELIAL-CELLS; MEDROXYPROGESTERONE ACETATE; OSTEOPROTEGERIN-LIGAND; RECEPTOR ACTIVATOR; GLAND DEVELOPMENT; BONE METASTASIS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49269