Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort

Renée T Fortner; Danja Sarink; Helena Schock; Theron Johnson; Anne Tjønneland; Anja Olsen; Kim Overvad; Aurélie Affret; Mathilde His; Marie-Christine Boutron-Ruault; Heiner Boeing; Antonia Trichopoulou; Androniki Naska; Philippos Orfanos; Domenico Palli; Sabina Sieri; Amalia Mattiello; Rosario Tumino; Fulvio Ricceri; H Bas Bueno-de-Mesquita; Petra H M Peeters; Carla H Van Gils; Elisabete Weiderpass; Eiliv Lund; J Ramón Quirós; Antonio Agudo; Maria-José Sánchez; María-Dolores Chirlaque; Eva Ardanaz; Miren Dorronsoro; Tim Key; Kay-Tee Khaw; Sabina Rinaldi; Laure Dossus; Marc Gunter; Melissa A Merritt; Elio Riboli; Rudolf Kaaks

doi:10.1186/s12916-017-0786-8

Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort

Renée T Fortner, Danja Sarink, Helena Schock, Theron Johnson, Anne Tjønneland, Anja Olsen, Kim Overvad, Aurélie Affret, Mathilde His, Marie-Christine Boutron-Ruault, Heiner Boeing, Antonia Trichopoulou, Androniki Naska, Philippos Orfanos, Domenico Palli, Sabina Sieri, Amalia Mattiello, Rosario Tumino, Fulvio Ricceri, H Bas Bueno-de-MesquitaPetra H M Peeters, Carla H Van Gils, Elisabete Weiderpass, Eiliv Lund, J Ramón Quirós, Antonio Agudo, Maria-José Sánchez, María-Dolores Chirlaque, Eva Ardanaz, Miren Dorronsoro, Tim Key, Kay-Tee Khaw, Sabina Rinaldi, Laure Dossus, Marc Gunter, Melissa A Merritt, Elio Riboli, Rudolf Kaaks

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Abstract

BACKGROUND: Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study.

METHODS: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n = 1622; ER-, n = 386), matched 1:1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.

RESULTS: The associations between OPG and ER+ and ER- breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER- breast cancer (top vs. bottom tertile RR = 1.93 [95% CI 1.24-3.02]; p trend = 0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER- disease did not differ by menopausal status at blood collection (p het = 0.97), and we observed no heterogeneity by HT use at blood collection (p het ≥ 0.43) or age at breast cancer diagnosis (p het ≥ 0.30).

CONCLUSIONS: This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER- breast cancer.

Original language	English
Article number	26
Journal	BMC Medicine
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s12916-017-0786-8
Publication status	Published - 8 Feb 2017

Keywords

Breast cancer
Estrogen receptor
Hormone receptor
Osteoprotegerin
Progesterone receptor
RANK axis

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Fortner, R. T., Sarink, D., Schock, H., Johnson, T., Tjønneland, A., Olsen, A., Overvad, K., Affret, A., His, M., Boutron-Ruault, M.-C., Boeing, H., Trichopoulou, A., Naska, A., Orfanos, P., Palli, D., Sieri, S., Mattiello, A., Tumino, R., Ricceri, F., ... Kaaks, R. (2017). Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort. BMC Medicine, 15(1), Article 26. https://doi.org/10.1186/s12916-017-0786-8

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title = "Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort",

abstract = "BACKGROUND: Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study.METHODS: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n = 1622; ER-, n = 386), matched 1:1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.RESULTS: The associations between OPG and ER+ and ER- breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER- breast cancer (top vs. bottom tertile RR = 1.93 [95% CI 1.24-3.02]; p trend = 0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER- disease did not differ by menopausal status at blood collection (p het = 0.97), and we observed no heterogeneity by HT use at blood collection (p het ≥ 0.43) or age at breast cancer diagnosis (p het ≥ 0.30).CONCLUSIONS: This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER- breast cancer.",

keywords = "Breast cancer, Estrogen receptor, Hormone receptor, Osteoprotegerin , Progesterone receptor, RANK axis",

author = "Fortner, {Ren{\'e}e T} and Danja Sarink and Helena Schock and Theron Johnson and Anne Tj{\o}nneland and Anja Olsen and Kim Overvad and Aur{\'e}lie Affret and Mathilde His and Marie-Christine Boutron-Ruault and Heiner Boeing and Antonia Trichopoulou and Androniki Naska and Philippos Orfanos and Domenico Palli and Sabina Sieri and Amalia Mattiello and Rosario Tumino and Fulvio Ricceri and Bueno-de-Mesquita, {H Bas} and Peeters, {Petra H M} and {Van Gils}, {Carla H} and Elisabete Weiderpass and Eiliv Lund and Quir{\'o}s, {J Ram{\'o}n} and Antonio Agudo and Maria-Jos{\'e} S{\'a}nchez and Mar{\'i}a-Dolores Chirlaque and Eva Ardanaz and Miren Dorronsoro and Tim Key and Kay-Tee Khaw and Sabina Rinaldi and Laure Dossus and Marc Gunter and Merritt, {Melissa A} and Elio Riboli and Rudolf Kaaks",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = feb,

day = "8",

doi = "10.1186/s12916-017-0786-8",

language = "English",

volume = "15",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central",

number = "1",

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Fortner, RT, Sarink, D, Schock, H, Johnson, T, Tjønneland, A, Olsen, A, Overvad, K, Affret, A, His, M, Boutron-Ruault, M-C, Boeing, H, Trichopoulou, A, Naska, A, Orfanos, P, Palli, D, Sieri, S, Mattiello, A, Tumino, R, Ricceri, F, Bueno-de-Mesquita, HB, Peeters, PHM, Van Gils, CH, Weiderpass, E, Lund, E, Quirós, JR, Agudo, A, Sánchez, M-J, Chirlaque, M-D, Ardanaz, E, Dorronsoro, M, Key, T, Khaw, K-T, Rinaldi, S, Dossus, L, Gunter, M, Merritt, MA, Riboli, E & Kaaks, R 2017, 'Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort', BMC Medicine, vol. 15, no. 1, 26. https://doi.org/10.1186/s12916-017-0786-8

TY - JOUR

T1 - Osteoprotegerin and breast cancer risk by hormone receptor subtype

T2 - a nested case-control study in the EPIC cohort

AU - Fortner, Renée T

AU - Sarink, Danja

AU - Schock, Helena

AU - Johnson, Theron

AU - Tjønneland, Anne

AU - Olsen, Anja

AU - Overvad, Kim

AU - Affret, Aurélie

AU - His, Mathilde

AU - Boutron-Ruault, Marie-Christine

AU - Boeing, Heiner

AU - Trichopoulou, Antonia

AU - Naska, Androniki

AU - Orfanos, Philippos

AU - Palli, Domenico

AU - Sieri, Sabina

AU - Mattiello, Amalia

AU - Tumino, Rosario

AU - Ricceri, Fulvio

AU - Bueno-de-Mesquita, H Bas

AU - Peeters, Petra H M

AU - Van Gils, Carla H

AU - Weiderpass, Elisabete

AU - Lund, Eiliv

AU - Quirós, J Ramón

AU - Agudo, Antonio

AU - Sánchez, Maria-José

AU - Chirlaque, María-Dolores

AU - Ardanaz, Eva

AU - Dorronsoro, Miren

AU - Key, Tim

AU - Khaw, Kay-Tee

AU - Rinaldi, Sabina

AU - Dossus, Laure

AU - Gunter, Marc

AU - Merritt, Melissa A

AU - Riboli, Elio

AU - Kaaks, Rudolf

PY - 2017/2/8

Y1 - 2017/2/8

N2 - BACKGROUND: Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study.METHODS: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n = 1622; ER-, n = 386), matched 1:1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.RESULTS: The associations between OPG and ER+ and ER- breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER- breast cancer (top vs. bottom tertile RR = 1.93 [95% CI 1.24-3.02]; p trend = 0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER- disease did not differ by menopausal status at blood collection (p het = 0.97), and we observed no heterogeneity by HT use at blood collection (p het ≥ 0.43) or age at breast cancer diagnosis (p het ≥ 0.30).CONCLUSIONS: This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER- breast cancer.

AB - BACKGROUND: Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study.METHODS: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n = 1622; ER-, n = 386), matched 1:1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression.RESULTS: The associations between OPG and ER+ and ER- breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER- breast cancer (top vs. bottom tertile RR = 1.93 [95% CI 1.24-3.02]; p trend = 0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER- disease did not differ by menopausal status at blood collection (p het = 0.97), and we observed no heterogeneity by HT use at blood collection (p het ≥ 0.43) or age at breast cancer diagnosis (p het ≥ 0.30).CONCLUSIONS: This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER- breast cancer.

KW - Breast cancer

KW - Estrogen receptor

KW - Hormone receptor

KW - Osteoprotegerin

KW - Progesterone receptor

KW - RANK axis

U2 - 10.1186/s12916-017-0786-8

DO - 10.1186/s12916-017-0786-8

M3 - Article

C2 - 28173834

SN - 1741-7015

VL - 15

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 26

ER -

Osteoprotegerin and breast cancer risk by hormone receptor subtype: a nested case-control study in the EPIC cohort

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