Genetically obese MMTV-TGF-alpha/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-alpha (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-alpha and Lep strain mice were crossed to produce TGF-alpha/Lep(+)Lep(+) (homozygous lean), TGF-alpha/Lep(+)Lep(ob) (heterozygous lean) and TGF-alpha/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-alpha/Lep(ob)Lep(ob) mice failed to develop MTs. MTs were detected between 48 and 104 weeks of age for 26/39 TGF-alpha/Lep(+)Lep(ob) mice and for 19/38 TGF-alpha/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-alpha/Lep(+)Lep(ob) mice (p < 0.09). There were significant effects of both genotype and MTs on final body weight, that is, TGF-alpha/Lep(+)Lep(ob) mice weighed more than homozygous lean mice, and mice with MTs weighed more than those without MTs. TGF-alpha/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.