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ORIGINAL RESEARCH ARTICLE

Leptin Receptor–Deficient MMTV-TGF-/Lepr^dbLepr^db Female Mice Do Not Develop Oncogene-Induced Mammary Tumors

Margot P. Cleary^*,1, Subhash C. Juneja, Frederick C. Phillips^*, Xin Hu^*, Joseph P. Grande and Nita J. Maihle^,2

^* Hormel Institute, University of Minnesota, 801 16^th Avenue NE, Austin, Minnesota 55912; and Departments of Laboratory Medicine and Pathology and Biochemistry and Molecular Biology, Mayo Foundation, Rochester, Minnesota 55905

To whom requests for reprints should be addressed at ¹ Hormel Institute, University of Minnesota, 801 16^th Avenue N.E., Austin, MN 55912. E-mail: mpcleary{at}hi.umn.edu

Being overweight is a risk factor for postmenopausal breast cancer and is associated with an increased incidence and shortened latency of spontaneous and chemically induced mammary tumors in rodents. However, leptin-deficient obese Lep^obLep^ob female mice have reduced incidences of spontaneous and oncogene-induced mammary tumors. Of interest, leptin enhances the proliferation of human breast cancer cell lines in which leptin receptors are expressed, which suggests that leptin signaling plays a role in tumor development. We evaluated oncogene-induced mammary tumor development in obese MMTV-TGF-/Lepr^dbLepr^db mice that exhibit a defect in OB-Rb, which is considered to be the major signaling isoform of the leptin receptor. Lepr and MMTV-TGF- mice were crossed, and the offspring were genotyped for oncogene expression and the determination of Lepr status. Lean MMTV-TGF-/Lepr⁺Lepr⁺ (homozygous) and MMTV-TGF-/Lepr⁺Lepr^db (heterozygous) mice and obese MMTV-TGF-/Lepr^dbLepr^db mice were monitored until age 104 weeks. Body weights of MMTV-TGF-/ Lepr^dbLepr^db mice were significantly heavier than those of the lean groups. No mammary tumors were detected in MMTV-TGF-/Lepr^dbLepr^db mice, whereas the incidence of mammary tumors in MMTV-TGF-/Lepr⁺Lepr⁺ and MMTV-TGF-/ Lepr⁺Lepr^db mice was 69% and 82%, respectively. Examination of mammary tissue whole mounts indicated an absence of duct formation and branching for MMTV-TGF-/Lepr^dbLepr^db mice. Both age at mammary tumor detection and tumor burden (tumors/mouse and tumor weights) were similar for the lean genotypes. Serum leptin levels of MMTV-TGF-/Lepr^dbLepr^db mice were 12–20-fold higher than levels of lean mice. Thus, despite elevated serum leptin levels, leptin receptor–deficient MMTV-TGF-/Lepr^dbLepr^db mice do not develop mammary tumors. This study provides additional evidence that leptin and its cognate receptor may be involved in mammary tumorigenesis.

Key Words: leptin • leptin receptor • breast cancer • mice • obesity • OB-Rb

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