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Total and High-Molecular-Weight Adiponectin in Breast Cancer: In Vitro and in Vivo Studies

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/or high-molecular-weight (HMW) adiponectin levels may underlie this association.

Methods: We measured serum total and HMW adiponectin in a hospital-based case-control study of 74 female breast cancer patients and 76 controls. In parallel, expression of adiponectin and its receptors AdipoR1/R2 were measured in tissue samples using RT-PCR, and protein expression of AdipoR1/R2 was localized and quantified using immunohistochemistry. Finally, we documented AdipoR1/R2 expression in several breast cancer cell lines and studied adiponectin signaling and the effect of adiponectin on proliferation in the 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 became stronger after adjustment for age, body mass index, and hormonal and reproductive factors (P = 0.02). Modeling HMW instead of total adiponectin produced similar results and did not offer any additional predictive value. Breast cancer cells expressed AdipoR1/R2 but not adiponectin. Expression of AdipoR1, but not AdipoR2, was higher in tumor tissue than both adjacent and control tissues. Exposure of T47D cells to adiponectin significantly inhibited the percentage of viable cells to 86% and proliferation to 66% but had no effect on apoptosis. These effects were associated with activation of ERK1/2 but not AMP-activated protein kinase or p38MAPK.

Conclusion: These studies suggest that adiponectin may act as a biomarker of carcinogenesis and may constitute a molecular link between obesity and breast cancer.

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