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Growth Hormone-Deficient Dwarf Animals Are Resistant to Dimethylbenzanthracine (DMBA)-Induced Mammary Carcinogenesis

Department of Physiology and Pharmacology (M.M.R., R.L.I., A.B.C., A.H.N., W.E.S.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1083; Department of Pathology (J.M.C.), Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157; Director, National Hormone and Peptide Program (A.F.P.), Harbor-UCLA Medical Center, Torrance, California 90509

Increased plasma IGF-1 has consistently been associated with a variety of human cancers, whereas reduced levels of IGF-1 are associated with increased lifespan in other species. However, the aforementioned relationships are correlational or are derived from animal models that are not specific for growth hormone/IGF-1 excess or deficiency. This study was designed to assess the effects of physiological changes in growth hormone and IGF-1 expression on dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. At 50 days of age, female heterozygous (dw/+) and growth hormone deficient dwarf (dw/dw) rats of the Lewis strain received a single dose of DMBA (80 µg/g of body weight) via oral gavage. Animals were assigned to one of four experimental groups: a) heterozygous animals (normal size), b) dwarf animals administered vehicle, c) dwarf animals administered low levels of porcine growth hormone (50 µg twice daily), and d) dwarf animals administered high levels of porcine growth hormone (200 µg twice daily). At study termination, heterozygous animals exhibited a 70% incidence of mammary tumors, whereas no tumors were observed in saline-treated dwarf animals. Administration of either 100 µg or 400 µg growth hormone/day resulted in a dose dependent increase in incidence of mammary tumors (83 and 100%, respectively). Furthermore, heterozygous animals exhibited 1.5 ± 0.25 tumors per tumor-bearing animal, whereas dwarf animals administered 100 µg and 400 µg growth hormone per day had 1.9 ± 0.63 and 3.4 ± 0.83 tumors per animal, respectively. The present study demonstrates that DMBA-induced carcinogenesis is dependent on critical plasma levels of growth hormone and IGF-1, and that growth hormone/IGF-1 deficient animals are resistant to DMBA-induced carcinogenesis.

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