Total and High-Molecular-Weight Adiponectin in Breast Cancer: In Vitro and in Vivo Studies
Antje Körner,
Kalliopi Pazaitou-Panayiotou,
Theodoros Kelesidis,
Iosif Kelesidis,
Catherine J. Williams,
Athina Kaprara,
John Bullen,
Anke Neuwirth,
Sofia Tseleni,
Nicholas Mitsiades,
Wieland Kiess and
Christos S. Mantzoros
University Hospital for Children and Adolescents (A.Kö, W.K.), University of Leipzig, D-04103 Leipzig, Germany; Division of Endocrinology-Endocrine Oncology (K.P.-P., A.Ka.), Theagenio Cancer Hospital, GR-54124 Thessaloniki, Greece; Division of Endocrinology, Diabetes, and Metabolism (T.K., I.K., C.J.W., J.B., A.N., N.M., C.S.M.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215; and Department of Pathology (S.T.), University of Athens Medical School, GR-15784 Athens, Greece
Address all correspondence and requests for reprints to: Christos S. Mantzoros, M.D., Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Stoneman 816, Boston, Massachusetts 02215. E-mail: cmantzor{at}bidmc.harvard.edu.
Background: Obesity is a major risk factor for breast cancer.We hypothesized that obesity-induced decreases in total and/orhigh-molecular-weight (HMW) adiponectin levels may underliethis association.
Methods: We measured serum total and HMW adiponectin in a hospital-basedcase-control study of 74 female breast cancer patients and 76controls. In parallel, expression of adiponectin and its receptorsAdipoR1/R2 were measured in tissue samples using RT-PCR, andprotein expression of AdipoR1/R2 was localized and quantifiedusing immunohistochemistry. Finally, we documented AdipoR1/R2expression in several breast cancer cell lines and studied adiponectinsignaling and the effect of adiponectin on proliferation inthe T47D breast cancer cell line in vitro.
Results: Women with the highest adiponectin levels had a 65%reduced risk of breast cancer (P = 0.04). This association becamestronger after adjustment for age, body mass index, and hormonaland reproductive factors (P = 0.02). Modeling HMW instead oftotal adiponectin produced similar results and did not offerany additional predictive value. Breast cancer cells expressedAdipoR1/R2 but not adiponectin. Expression of AdipoR1, but notAdipoR2, was higher in tumor tissue than both adjacent and controltissues. Exposure of T47D cells to adiponectin significantlyinhibited the percentage of viable cells to 86% and proliferationto 66% but had no effect on apoptosis. These effects were associatedwith activation of ERK1/2 but not AMP-activated protein kinaseor p38MAPK.
Conclusion: These studies suggest that adiponectin may act asa biomarker of carcinogenesis and may constitute a molecularlink between obesity and breast cancer.
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