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Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer.
- Source :
-
Oncotarget [Oncotarget] 2017 Jan 17; Vol. 8 (3), pp. 3811-3825. - Publication Year :
- 2017
-
Abstract
- Breast cancer is the most common female cancer, affecting approximately one in eight women during their lifetime in North America and Europe. Receptor Activator of NF-kB Ligand (RANKL), its receptor RANK and the natural antagonist osteoprotegerin (OPG) are essential regulators of bone resorption. We have initially shown that RANKL/RANK are essential for hormone-driven mammary epithelial proliferation in pregnancy and RANKL/RANK have been implicated in mammary stem cell biology. Using genetic mouse-models, we and others identified the RANKL/RANK system as a key regulator of sex hormone, BRCA1-mutation, and oncogene-driven breast cancer and we proposed that RANKL/RANK might be involved in the initiation of breast tumors. We now report that in postmenopausal women without known genetic predisposition, high RANKL and progesterone serum levels stratify a subpopulation of women at high risk of developing breast cancer 12-24 months before diagnosis (5.33-fold risk, 95%CI 1.5-25.4; P=0.02). In women with established breast cancer, we demonstrate that RANKL/OPG ratios change dependent on the presence of circulating tumor cells (CTCs). Finally, we show in a prospective human breast cancer cohort that alterations in RANKL/OPG ratios are significantly associated with breast cancer manifestation. These data indicate that the RANKL/RANK/OPG system is deregulated in post-menopausal women at high risk for breast cancer and in women with circulating tumor cells. Thus, serum levels of RANKL/OPG are potentially indicative of predisposition and progression of breast cancer in humans. Advancement of our findings towards clinical application awaits prior validation in independent patient cohorts.
- Subjects :
- Biomarkers, Tumor blood
Breast Neoplasms blood
Early Detection of Cancer
Female
Gene Expression Regulation, Neoplastic
Humans
Postmenopause
Prospective Studies
Receptor Activator of Nuclear Factor-kappa B blood
Up-Regulation
Breast Neoplasms metabolism
Neoplastic Cells, Circulating metabolism
Osteoprotegerin blood
Progesterone blood
RANK Ligand blood
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28002811
- Full Text :
- https://doi.org/10.18632/oncotarget.14013