Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation.
Insulin-like growth factor I (IGF-I) is a potent breast cancer mitogen. Growth hormone (GH) up-regulates hepatic IGF-I gene expression and circulating IGF-I level. Tissue IGF bioactivity is influenced not only by circulating IGF-I and IGF-II levels but also by autocrine and paracrine production of these growth factors and by IGF binding proteins. There is considerable person-to-person variability in GH-IGF-I physiology. Both laboratory and epidemiological data are consistent with the hypothesis that the host GH-IGF-I axis influences breast cancer behavior, but such an effect has not been directly demonstrated. To determine whether breast cancer growth in an in vivo model is influenced by the host GH-IGF-I axis, we compared the growth of human MCF-7 breast cancer cells in control mice to that in mice homozygous for lit, a missense mutation resulting in loss of function of the pituitary GH-releasing hormone receptor and secondary suppression of GH and IGF-I. Breast cancer growth was significantly reduced in lit/lit animals compared to control hosts [tumor size (mean +/- SD) on day 39,444 +/- 82 versus 845 +/- 444 mm3, respectively; P < 0.001, Mann-Whitney U test]. These data demonstrate that in our model, host GH-IGF-I axis physiology plays a role in determining breast cancer behavior. The results a) suggest that patient-to-patient variability in GH-IGF-I physiology may contribute to the large variability between patients regarding breast cancer behavior, and b) motivate clinical trials of novel hormonal treatment strategies that target the GH-IGF-I axis.
Yang
X F
XF
Lady Davis Research Institute, McGill University, Montreal, Quebec, Canada.
Beamer
W G
WG
Huynh
H
H
Pollak
M
M
D000818:Animals; D005260:Female; D013006:Growth Hormone / Q000502:physiology*; D006720:Homozygote; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D018013:Receptors, Neuropeptide / Q000502:physiology; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000502:physiology; D014183:Transplantation, Heterologous
D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C048250:somatotropin releasing hormone receptor