Leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) female mice do not develop oncogene-induced mammary tumors.
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(ob)Lep(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-alpha/Lepr(db)Lepr(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-alpha mice were crossed, and the offspring were genotyped for oncogene expression and the determination of Lepr status. Lean MMTV-TGF-alpha/Lepr(+)Lepr(+) (homozygous) and MMTV-TGF-alpha/Lepr(+)Lepr(db) (heterozygous) mice and obese MMTV-TGF-alpha/Lepr(db)Lepr(db) mice were monitored until age 104 weeks. Body weights of MMTV-TGF-alpha/ Lepr(db)Lepr(db) mice were significantly heavier than those of the lean groups. No mammary tumors were detected in MMTV-TGF-alpha/Lepr(db)Lepr(db) mice, whereas the incidence of mammary tumors in MMTV-TGF-alpha/Lepr(+)Lepr(+) and MMTV-TGF-alpha/ 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-alpha/Lepr(db)Lepr(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-alpha/Lepr(db)Lepr(db) mice were 12-20-fold higher than levels of lean mice. Thus, despite elevated serum leptin levels, leptin receptor-deficient MMTV-TGF-alpha/Lepr(db)Lepr(db) mice do not develop mammary tumors. This study provides additional evidence that leptin and its cognate receptor may be involved in mammary tumorigenesis.
Cleary
Margot P
MP
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA. mpcleary@hi.umn.edu
Juneja
Subhash C
SC
Phillips
Frederick C
FC
Hu
Xin
X
Grande
Joseph P
JP
Maihle
Nita J
NJ
D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D005260:Female; D020738:Leptin / Q000097:blood / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000502:physiology*; D054411:Receptors, Leptin; D016019:Survival Analysis; D016211:Transforming Growth Factor alpha / Q000235:genetics
C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D016211:Transforming Growth Factor alpha; C515447:leptin receptor, mouse