Cleary Margot P, Juneja Subhash C, Phillips Frederick C, Hu Xin, Grande Joseph P, Maihle Nita J
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Exp Biol Med (Maywood). 2004 Feb;229(2):182-93. doi: 10.1177/153537020422900207.
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.
超重是绝经后乳腺癌的一个风险因素，并且与啮齿动物自发性和化学诱导性乳腺肿瘤的发病率增加及潜伏期缩短有关。然而，瘦素缺乏的肥胖Lep(ob)Lep(ob)雌性小鼠自发性和癌基因诱导性乳腺肿瘤的发病率降低。有趣的是，瘦素可增强表达瘦素受体的人乳腺癌细胞系的增殖，这表明瘦素信号传导在肿瘤发展中起作用。我们评估了肥胖的MMTV-TGF-α/Lepr(db)Lepr(db)小鼠（其OB-Rb存在缺陷，OB-Rb被认为是瘦素受体的主要信号亚型）中癌基因诱导的乳腺肿瘤发展情况。将Lepr和MMTV-TGF-α小鼠进行杂交，对后代进行基因分型以检测癌基因表达并确定Lepr状态。对瘦的MMTV-TGF-α/Lepr(+)Lepr(+)（纯合子）和MMTV-TGF-α/Lepr(+)Lepr(db)（杂合子）小鼠以及肥胖的MMTV-TGF-α/Lepr(db)Lepr(db)小鼠进行监测直至104周龄。MMTV-TGF-α/Lepr(db)Lepr(db)小鼠的体重显著高于瘦的组。在MMTV-TGF-α/Lepr(db)Lepr(db)小鼠中未检测到乳腺肿瘤，而MMTV-TGF-α/Lepr(+)Lepr(+)和MMTV-TGF-α/Lepr(+)Lepr(db)小鼠的乳腺肿瘤发病率分别为69%和82%。对乳腺组织整装片的检查表明，MMTV-TGF-α/Lepr(db)Lepr(db)小鼠不存在导管形成和分支。对于瘦的基因型，检测到乳腺肿瘤的年龄和肿瘤负荷（肿瘤/小鼠及肿瘤重量）相似。MMTV-TGF-α/Lepr(db)Lepr(db)小鼠的血清瘦素水平比瘦小鼠的水平高12至20倍。因此，尽管血清瘦素水平升高，但瘦素受体缺陷的MMTV-TGF-α/Lepr(db)Lepr(db)小鼠并未发生乳腺肿瘤。这项研究提供了额外的证据，表明瘦素及其同源受体可能参与乳腺肿瘤的发生。
