Olivia Moran1,2, Tasnim Zaman1,3, Andrea Eisen4, Rochelle Demsky5,6, Kristina Blackmore7, Julia A Knight8,9, Christine Elser10, Ophira Ginsburg11, Kevin Zbuk12, Martin Yaffe13, Steven A Narod1,9, Leonardo Salmena3,14, Joanne Kotsopoulos15,16,17. 1. Women's College Research Institute, Women's College Hospital, 76 Grenville St., 6th Floor, Toronto, ON, M5S 1B2, Canada. 2. Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada. 3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. 4. Toronto-Sunnybrook Regional Cancer Center, Toronto, ON, Canada. 5. Division of Gynecologic Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada. 6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. 7. Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada. 8. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. 9. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. 10. Division of Medical Oncology and Hematology, Department of Medicine, Mount Sinai Hospital and The Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada. 11. Laura and Isaac Perlmutter Cancer Centre, NYU Langone Medical Center, NYU School of Medicine, New York, NY, USA. 12. Department of Oncology, McMaster University, Hamilton, ON, Canada. 13. Department of Medical Biophysics, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada. 14. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 15. Women's College Research Institute, Women's College Hospital, 76 Grenville St., 6th Floor, Toronto, ON, M5S 1B2, Canada. joanne.kotsopoulos@wchospital.ca. 16. Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada. joanne.kotsopoulos@wchospital.ca. 17. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. joanne.kotsopoulos@wchospital.ca.
Abstract
PURPOSE: Mammographic density is a risk factor for breast cancer but the mechanism behind this association is unclear. The receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) pathway has been implicated in the development of breast cancer. Given the role of RANK signaling in mammary epithelial cell proliferation, we hypothesized this pathway may also be associated with mammographic density. Osteoprotegerin (OPG), a decoy receptor for RANKL, is known to inhibit RANK signaling. Thus, it is of interest to evaluate whether OPG levels modify breast cancer risk through mammographic density. METHODS: We quantified serum OPG levels in 57 premenopausal and 43 postmenopausal women using an enzyme-linked immunosorbent assay (ELISA). Cumulus was used to measure percent density, dense area, and non-dense area for each mammographic image. Subjects were classified into high versus low OPG levels based on the median serum OPG level in the entire cohort (115.1 pg/mL). Multivariate models were used to assess the relationship between serum OPG levels and the measures of mammographic density. RESULTS: Serum OPG levels were not associated with mammographic density among premenopausal women (P ≥ 0.42). Among postmenopausal women, those with low serum OPG levels had higher mean percent mammographic density (20.9% vs. 13.7%; P = 0.04) and mean dense area (23.4 cm2 vs. 15.2 cm2; P = 0.02) compared to those with high serum OPG levels after covariate adjustment. CONCLUSIONS: These findings suggest that low OPG levels may be associated with high mammographic density, particularly in postmenopausal women. Targeting RANK signaling may represent a plausible, non-surgical prevention option for high-risk women with high mammographic density, especially those with low circulating OPG levels.
PURPOSE: Mammographic density is a risk factor for breast cancer but the mechanism behind this association is unclear. The receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) pathway has been implicated in the development of breast cancer. Given the role of RANK signaling in mammary epithelial cell proliferation, we hypothesized this pathway may also be associated with mammographic density. Osteoprotegerin (OPG), a decoy receptor for RANKL, is known to inhibit RANK signaling. Thus, it is of interest to evaluate whether OPG levels modify breast cancer risk through mammographic density. METHODS: We quantified serum OPG levels in 57 premenopausal and 43 postmenopausal women using an enzyme-linked immunosorbent assay (ELISA). Cumulus was used to measure percent density, dense area, and non-dense area for each mammographic image. Subjects were classified into high versus low OPG levels based on the median serum OPG level in the entire cohort (115.1 pg/mL). Multivariate models were used to assess the relationship between serum OPG levels and the measures of mammographic density. RESULTS: Serum OPG levels were not associated with mammographic density among premenopausal women (P ≥ 0.42). Among postmenopausal women, those with low serum OPG levels had higher mean percent mammographic density (20.9% vs. 13.7%; P = 0.04) and mean dense area (23.4 cm2 vs. 15.2 cm2; P = 0.02) compared to those with high serum OPG levels after covariate adjustment. CONCLUSIONS: These findings suggest that low OPG levels may be associated with high mammographic density, particularly in postmenopausal women. Targeting RANK signaling may represent a plausible, non-surgical prevention option for high-risk women with high mammographic density, especially those with low circulating OPG levels.
Entities:
Keywords:
Breast cancer; Mammographic density; Osteoprotegerin (OPG); RANK ligand (RANKL); Receptor activator of nuclear factor κB (RANK)
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