Erythropoietin receptor expression and correlation to tamoxifen response and prognosis in breast cancer.
OBJECTIVE
The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen.


METHODS
EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS).


RESULTS
EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor-positive/progesterone receptor-positive (ER(+)/PR(+)) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER(+) tumors with high EPOR expression.


CONCLUSIONS
EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER(+)/PR(+) tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior.
Larsson
Anna-Maria
AM
Center for Molecular Pathology, Department of Laboratory Medicine, University Hospital MAS, Malmö, Sweden.
Jirström
Karin
K
Fredlund
Erik
E
Nilsson
Sofie
S
Rydén
Lisa
L
Landberg
Göran
G
Påhlman
Sven
S
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000096:biosynthesis*; D013629:Tamoxifen / Q000627:therapeutic use*; D046888:Tissue Array Analysis
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D013629:Tamoxifen; D004921:Erythropoietin