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.
Highlights
RESULTSReceptor Activator of NF-kB Ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin (OPG) are essential for the development and activation of osteoclasts [1, 2]
We show that increased progesterone and RANKL serum levels stratify a subgroup of postmenopausal women without known genetic predispositions that exhibit a ~5 fold increased risk of developing breast cancer 12-24 months before cancer diagnosis
Our findings that an increased RANKL/OPG ratio > 12 months prior to breast cancer development is consistent with findings from meta-analysis by Key et al that showed that sex steroid hormone levels well in advance of breast cancer diagnosis are more significantly associated with breast cancer risk compared with hormone levels analyzed closer to diagnosis [30]
Summary
RANKL (receptor activator of NF-kB ligand), its receptor RANK, and the decoy receptor osteoprotegerin (OPG) are essential for the development and activation of osteoclasts [1, 2]. Women within the high progesterone and high serum RANKL/OPG ratio group carried a 5.3 (95% CI 1.5 - 25.4, p = 0.0169) fold risk to develop breast cancer 12-24 months after diagnosis (Table 4). We analyzed the group of UKCTOCS participants who developed breast cancer within 12 months (BC < 12 months) Among this cohort high progesterone/high RANKL levels were not associated with an increased incidence of breast cancer (Figure 2, Table 4). We rather observed a progesteroneindependent reduction in RANKL and increase in OPG serum levels with breast cancer manifestation resulting in significant decrease in the RANKL-to-OPG ratio compared to UKCTOCS participants who never developed breast cancer (Figure 3A). Our data in two different human prospective breast cancer cohorts indicate that alterations in RANKL/ OPG ratios are significantly associated with breast cancer manifestation
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