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Progesterone/RANKL is a major regulatory axis in the human breast
- Source :
- Science translational medicine, Science Translational Medicine, Vol. 5, No 182 (2013) pp. 1-10
- Publication Year :
- 2013
-
Abstract
- Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor kB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR + breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved.<br />National Center of Competence in Research Molecular Oncology, Oncosuisse (SNF-3100A0112090/SNF-31003-138065); Marie-Curie incoming fellowship; European Union (115188)
- Subjects :
- musculoskeletal diseases
medicine.medical_specialty
Cancer cells
In Vitro Techniques
medicine.disease_cause
Progesterone receptor
03 medical and health sciences
Paracrine signalling
0302 clinical medicine
Breast cancer
Internal medicine
ddc:570
medicine
Humans
Progesterones
Breast
Progesterone
030304 developmental biology
Breast epithelium
0303 health sciences
Breast development
biology
business.industry
RANK Ligand
RANKL
General Medicine
medicine.disease
3. Good health
Endocrinology
Denosumab
Receptor activator of nuclear factor
030220 oncology & carcinogenesis
biology.protein
RNA
Female
business
Carcinogenesis
Receptors, Progesterone
medicine.drug
Subjects
Details
- ISSN :
- 19466242 and 19466234
- Volume :
- 5
- Issue :
- 182
- Database :
- OpenAIRE
- Journal :
- Science translational medicine
- Accession number :
- edsair.doi.dedup.....b76f7b12863e73319ddc193abf0103bf