Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer

Kiechl, Stefan; Schramek, Daniel; Widschwendter, Martin; Fourkala, Evangelia‐Ourania; Zaikin, Alexey; Jones, Allison; Jaeger, Bernadette; Rack, Brigitte; Janni, W; Scholz, Christoph; Willeit, Johann; Weger, Siegfried; Mayr, Agnes; Teschendorff, Andrew E.; Rosenthal, Adam N.; Fraser, Lindsay; Philpott, Susan; Dubeau, Louis; Keshtgar, Mohammed; Roylance, Rebecca; Jacobs, Ian; Menon, Usha; Schett, Georg; Penninger, Josef

doi:10.18632/oncotarget.14013

Cited by 47 publications

(36 citation statements)

References 38 publications

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“…In the past years, a role of RANKL in the pathogenesis of progestin-driven mammary carcinoma has been suggested (13,14). In postmenopausal women, high RANKL and progesterone serum levels stratify a subpopulation of women that are at high risk of developing breast cancer and RANKL/OPG ratios change depending on the presence of CTCs in patients with established breast cancer (38). A recent paper showed that low RANKL mRNA in early breast cancer tissue is associated with an increased risk of relapse and metastases (39).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Rachner

Kasimir‐Bauer

Göbel

et al. 2019

Clinical Cancer Research

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Purpose: We assessed serum concentrations of the receptor activator of NFkB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG), two proteins implicated in the development and progression of breast cancer, in 509 patients with primary, nonmetastatic breast cancer. Then the results were evaluated with regards to the occurrence of bone metastases, the presence of disseminated tumor cells (DTC) in the bone marrow, survival, and risk of developing metastatic disease.Experimental Design: Before surgery, two bone marrow aspirates were analyzed for DTC using density centrifugation followed by immunocytochemistry (pan-cytokeratin antibody A45-B/B3). RANKL and OPG levels in the serum were measured by ELISA.Results: RANKL levels were significantly lower in women >60 years (P < 0.0001) and RANKL/OPG ratios higher in lymph node-positive patients (P < 0.05). High OPG serum levels were associated with a higher risk of death from breast cancer [HR 1.94; 95% confidence interval (CI) 1.23-3.07; P ¼ 0.005] and OPG was an independent prognostic marker for breast cancer-specific survival (BCSS; multivariate analyses, P ¼ 0.035). RANKL levels were 33% higher (P < 0.0001) in DTC pos patients (41%), whereas high levels were associated with a significantly better BCSS in DTC neg patients as compared with low levels (HR 0.524; 95% CI 0.30-0.95; P ¼ 0.04). RANKL serum levels were significantly increased in patients who developed bone metastases (P ¼ 0.01) and patients within the highest quartile of RANKL had a significantly increased risk of developing bone metastases compared with those in the lowest (HR 4.62; 95% CI 1.49-14.34; P ¼ 0.03).Conclusions: These findings warrant further investigation as they provide a rationale for novel diagnostic or therapeutic approaches.NOTE: Values of RANKL and OPG are given in pmol/L. RANKL/OPG is displayed as a ratio of the two values. Significant values (P < 0.05) are shown in bold.Rachner et al.

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Rachner

Kasimir‐Bauer

Göbel

et al. 2019

Clinical Cancer Research

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“…RANKL/RANK (receptor activator of NF‐kB ligand/receptor) signaling is a core pathway in the adult mammary gland and breast cancer. It is also a key downstream paracrine effector of progesterone (Gonzalez‐Suarez et al , ; Schramek et al , ; Tanos et al , ; Nolan et al , ; Sigl et al , ; Kiechl et al , ). RANKL‐ and RANK‐deficient mice do not lactate due to defective alveolar development (Fata et al , ; Gonzalez‐Suarez et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…In otherwise histologically normal tissue of BRCA1 mutation carriers, luminal progenitors positive for RANK expression were shown to be highly proliferative, aberrant in DNA repair, and possessed a basal‐like breast cancer molecular signature (Nolan et al , ). High circulating RANKL levels correlate with increased breast cancer risk even in post‐menopausal women without a genetic predisposition (Kiechl et al , ). The RANKL axis is a druggable pathway, effectively inhibited in humans with the monoclonal antibody denosumab.…”

Section: Introductionmentioning

confidence: 99%

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Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

et al. 2019

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Breast cancer prevention is daunting, yet not an unsurmountable goal. Mammary stem and progenitors have been proposed as the cells‐of‐origin in breast cancer. Here, we present the concept of limiting these breast cancer precursors as a risk reduction approach in high‐risk women. A wealth of information now exists for phenotypic and functional characterization of mammary stem and progenitor cells in mouse and human. Recent work has also revealed the hormonal regulation of stem/progenitor dynamics as well as intrinsic lineage distinctions between mammary epithelial populations. Leveraging these insights, molecular marker‐guided chemoprevention is an achievable reality.

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“…Serum levels of soluble RANKL and OPG were measured using a sandwich and competitive enzyme immunoassay (Biomedica, Vienna, Austria), as previously described. According to the manufacturer, both the intra-assay and inter-assay coefficients of variation were lower than 10%, with detection limits of 0.14 pmol/L for soluble OPG and 0.08 pmol/L for soluble RANKL [21][22][23] .…”

Section: Assessment Of Breast Volumesmentioning

confidence: 99%

RANKL and OPG and their influence on breast volume changes during pregnancy in healthy women

Wunderle

Ruebner

Häberle

et al. 2020

Sci Rep

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Breast cancer risk is reduced by number of pregnancies and breastfeeding duration, however studies of breast changes during or after pregnancy are rare. Breast volume changes -although not linked to breast cancer risk -might be an interesting phenotype in this context for correlative studies, as changes of breast volume vary between pregnant women. Serum receptor activator of nuclear factor kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG) were measured prospectively before gestational week 12, and three-dimensional breast volume assessments were performed. A linear regression model including breast volume at the start of pregnancy, RANKL, OPG, and other factors was used to predict breast volume at term. The mean breast volume was 413 mL at gestational week 12, increasing by a mean of 99 mL up to gestational week 40. In addition to body mass index and breast volume at the beginning of pregnancy, RANKL and OPG appeared to influence breast volume with a mean increase by 32 mL (P = 0.04) and a mean reduction by 27 mL (P = 0.04), respectively. Linking the RANKL/RANK/OPG pathway with breast volume changes supports further studies aiming at analysing breast changes during pregnancy with regard to breast cancer risk.Many risk factors for breast cancer are either characteristics of a woman's reproductive history or are indirectly related to it 1,2 . The number of pregnancies and the duration of breastfeeding appear to play a pivotal role in this context 3 . Data from a large case-control study provide evidence that in Western industrialized countries, the cumulative lifetime risk of 6.3% up to the age of 70 could be reduced to 2.7% if the average number of full-term pregnancies was 6.5 instead of 2.5 and if the duration of breastfeeding was 24 months per lifetime instead of 8.7 months 3 .Interestingly, pregnancies appear to have an influence on breast cancer risk that is dependent on a woman's age at the first full-term pregnancy and on aging. In postmenopausal women, the protective effect of previous pregnancies is well established, regardless of age at the first full-term pregnancy. However, women who have their first child after the age of 35 have a transient increase in the risk of breast cancer up to 15 years after the pregnancy, in comparison with women of similar age without a pregnancy 4 . Although the effects of pregnancy and breastfeeding on breast cancer risk have been described in many epidemiological studies, little is known about macroscopic, microscopic or molecular changes during pregnancy that mediate the risk modification caused by pregnancies.Mammographic density as a risk factor for breast cancer correlates inversely with the number of pregnancies, as has been shown in several cross-sectional and case-control studies 5-11 . In a retrospective analysis with mammograms available before and shortly after a pregnancy, our group has shown that mammographic density decreases

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Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer

Cited by 47 publications

References 38 publications

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

RANKL and OPG and their influence on breast volume changes during pregnancy in healthy women

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