OPG and PgR show similar cohort-specific effects as prognostic factors in ER positive breast cancer

TY - JOUR

T1 - OPG and PgR show similar cohort-specific effects as prognostic factors in ER positive breast cancer

AU - Sänger, Nicole

AU - Ruckhäberle, Eugen

AU - Bianchini, Giampaolo

AU - Heinrich, Tomas

AU - Milde-Langosch, Karin

AU - Müller, Volkmar

AU - Rody, Achim

AU - Solomayer, Erich Franz

AU - Fehm, Tanja

AU - Holtrich, Uwe

AU - Becker, Sven

AU - Karn, Thomas

N1 - Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

PY - 2014

Y1 - 2014

N2 - The RANK/RANKL/OPG pathway is well known for bone destruction in skeletal metastases but has also been implicated in osteoclast-independent roles in tumorigenesis and de novo metastasis. Experimental data suggest contribution of progesterone to tumorigenesis may be mediated by RANKL. Importantly, modulation of this pathway became possible through the availability of denosumab, an artificial counterpart of OPG, but significant gaps remain in the translation of preclinical findings on the pathway. We analyzed gene expression of RANK, RANKL and OPG from 40 Affymetrix datasets encompassing 4467 primary breast cancers and focused on ER positive disease. We did not observe a significant prognostic value of RANK and RANKL mRNA expression. In contrast, OPG was associated with a better prognosis among 1941 ER positive cancers (HR 0.64, 95% CI 0.53-0.77; P < 0.0001) using a cutoff from its highly bimodal expression. We detected considerable heterogeneity regarding the prognostic value of OPG between different datasets. This heterogeneity could neither be attributed to technical reasons nor to differences in standard clinical parameters or treatments of the cohorts. Interestingly, the prognostic value of the progesterone receptor and of OPG showed similar cohort specific effects. Still both factors were no surrogates for each other but contributed independent prognostic value in multivariate analyses. Thus, both OPG and PgR are independently associated with good prognosis in ER positive breast cancer. However both markers share common cohort specific differences in contrast to proliferation markers as Ki67 which may be based on the underlying biology.

AB - The RANK/RANKL/OPG pathway is well known for bone destruction in skeletal metastases but has also been implicated in osteoclast-independent roles in tumorigenesis and de novo metastasis. Experimental data suggest contribution of progesterone to tumorigenesis may be mediated by RANKL. Importantly, modulation of this pathway became possible through the availability of denosumab, an artificial counterpart of OPG, but significant gaps remain in the translation of preclinical findings on the pathway. We analyzed gene expression of RANK, RANKL and OPG from 40 Affymetrix datasets encompassing 4467 primary breast cancers and focused on ER positive disease. We did not observe a significant prognostic value of RANK and RANKL mRNA expression. In contrast, OPG was associated with a better prognosis among 1941 ER positive cancers (HR 0.64, 95% CI 0.53-0.77; P < 0.0001) using a cutoff from its highly bimodal expression. We detected considerable heterogeneity regarding the prognostic value of OPG between different datasets. This heterogeneity could neither be attributed to technical reasons nor to differences in standard clinical parameters or treatments of the cohorts. Interestingly, the prognostic value of the progesterone receptor and of OPG showed similar cohort specific effects. Still both factors were no surrogates for each other but contributed independent prognostic value in multivariate analyses. Thus, both OPG and PgR are independently associated with good prognosis in ER positive breast cancer. However both markers share common cohort specific differences in contrast to proliferation markers as Ki67 which may be based on the underlying biology.

U2 - 10.1016/j.molonc.2014.04.003

DO - 10.1016/j.molonc.2014.04.003

M3 - SCORING: Journal article

C2 - 24785095

VL - 8

SP - 1196

EP - 1207

JO - MOL ONCOL

JF - MOL ONCOL

SN - 1574-7891

IS - 7

ER -