Genetically obese MMTV-TGF-α/Lep^ob Lep^ob female mice do not develop mammary tumors

Elevated body weight is a risk factor for postmenopausal breast cancer and is associated with increased incidence of spontaneous and chemically induced mammary tumors (MTs) in rodents. In this study, genetically obese Lep^ob Lep^ob female mice that overexpress human TGF-α (transforming growth factor-alpha) were used to assess the role of body weight on oncogene-induced MT development in comparison to lean counterparts. MMTV (mouse mammary tumor virus)-TGF-α and Lep strain mice were crossed to produce TGF-α/Lep⁺ Lep⁺ (homozygous lean), TGF-α/Lep⁺ Lep^ob (heterozygous lean) and TGF-α/Lep^ob Lep^ob (homozygous obese) genotypes. Body weights were determined weekly and mice palpated for the presence of MTs until 104 weeks of age. Despite their significantly higher body weight, obese TGF-α/Lep^ob Lep^ob mice failed to develop MTs. MTs were detected between 48 and 104 weeks of age for 26/39 TGF-α/Lep⁺ Lep^ob mice and for 19/38 TGF-α/Lep⁺ Lep⁺ mice between 67 and 104 weeks of age. Although MT incidence was not statistically different between the lean groups, age of MT detection tended to be younger for TGF-α/Lep⁺ Lep^ob mice (p < 0.09). There were significant effects of both genotype and MTs on final body weight, that is, TGF-α/Lep⁺ Lep^ob mice weighed more than homozygous lean mice, and mice with MTs weighed more than those without MTs. TGF-α/Lep^ob Lep^ob mice are not a good model to evaluate the effect of body weight on MT development possibly due to leptin deficiency. However, the finding that increased body weight is associated with increased oncogene-induced MT development within the normal weight range provides experimental support for the role of body weight in breast cancer.