© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 22, 1704-1711,
November 20, 2002
© 2002 Oxford University Press
ARTICLE |
Leptin—A Growth Factor in Normal and Malignant Breast Cells and for Normal Mammary Gland Development
Affiliations of authors: X. Hu, M. P. Cleary, The Hormel Institute, University of Minnesota, Austin; S. C. Juneja, N. J. Maihle, Departments of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
Correspondence to: Margot P. Cleary, Ph.D., The Hormel Institute, University of Minnesota, 801 16th Ave. NE, Austin, MN 55912 (e-mail: mpcleary{at}hi.umn.edu).
Background: Obesity is a risk factor for breast cancer in postmenopausal women. As body weight and fat mass increase, circulating leptin increases. Leptin is an adipocyte-derived cytokine that acts through the long form of its receptor, termed OB-Rb. To investigate whether leptin is associated with breast cancer, we determined the expression of OB-Rb in human breast epithelial HBL100 cells and human breast carcinoma-derived T-47D cells, determined whether leptin influenced the proliferation of these cells, and evaluated the structure of mammary tissue in genetically obese leptin-deficient LepobLepob and leptin receptor-deficient LeprdbLeprdb mice. Methods: Cell numbers and cell colony formation by HBL100 and T-47D cells were determined by anchorage-dependent and anchorage-independent growth assays. OB-Rb expression was examined by reverse transcription–polymerase chain reaction and immunoblot analyses. Expression of leptin signaling pathway components was evaluated with immunoblot and electrophoretic mobility shift assays. Mammary gland development in lean and obese mice was investigated in whole-mount studies. All statistical tests were two-sided. Results: Leptin enhanced anchorage-dependent proliferation by 138% (95% confidence interval [CI] = 108% to 169%) in T-47D cells and 50% (95% CI = 38% to 60%) in HBL100 cells. In both cell lines, OB-Rb was expressed, and leptin increased the expression of phosphorylated signal transducers and activators of transcription 3 (STAT3), phosphorylated extracellular signal-regulated kinase (ERK), and transcript activator protein 1 (AP-1). However, leptin increased anchorage-independent cell growth only in the breast cancer cell line (by 81% [95% CI = 62% to 101%] compared with untreated cells). Obese LepobLepob and LeprdbLeprdb mice had minimal epithelial development in the mature mammary gland compared with their lean counterparts. Conclusions: Leptin appears to be able to control the proliferation of both normal and malignant breast epithelial cells. Consequently, the leptin pathway should be further studied as a target for interventions to treat or prevent breast cancer.
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