OPG and PgR show similar cohort specific effects as prognostic factors in ER positive breast cancer.
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.
Department of Obstetrics and Gynecology, University Hospital Frankfurt, Germany.
Nicole
N
Sänger
Department of Obstetrics and Gynecology, Heinrich-Heine-University Duesseldorf, Germany.
Eugen
E
Ruckhäberle
Department of Medical Oncology, Ospedale San Raffaele, 20132 Milan, Italy.
Giampaolo
G
Bianchini
Department of Obstetrics and Gynecology, University Hospital Frankfurt, Germany.
Tomas
T
Heinrich
Department of Obstetrics and Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Karin
K
Milde-Langosch
Department of Obstetrics and Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Volkmar
V
Müller
Department of Obstetrics and Gynecology, University Hospital Lübeck, Germany.
Achim
A
Rody
Department of Obstetrics and Gynecology, University Medical School of Saarland, Homburg, Saar, Germany.
Erich Franz
EF
Solomayer
Department of Obstetrics and Gynecology, Heinrich-Heine-University Duesseldorf, Germany.
Tanja
T
Fehm
Department of Obstetrics and Gynecology, University Hospital Frankfurt, Germany.
Uwe
U
Holtrich
Department of Obstetrics and Gynecology, University Hospital Frankfurt, Germany.
Sven
S
Becker
Department of Obstetrics and Gynecology, University Hospital Frankfurt, Germany. Electronic address: t.karn@em.uni-frankfurt.de.
Thomas
T
Karn
D014408:Biomarkers, Tumor / Q000235:genetics; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D053244:Osteoprotegerin / Q000235:genetics*; D011379:Prognosis; D053245:RANK Ligand / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics; D011960:Receptors, Estrogen / Q000032:analysis*; D011980:Receptors, Progesterone / Q000235:genetics*; D059467:Transcriptome
D014408:Biomarkers, Tumor; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
Breast cancer; Cohort bias; Dataset pooling; Gene expression profiling; Osteoprotegerin; Progesteron receptor; RANK; RANKL