Advanced rat mammary cancers are growth hormone dependent.
Epidemiological studies suggest that the GH/IGF-I axis may promote human cancers. Animal models in which the GH/IGF-I axis can be controlled may be helpful in elucidating the role of these hormones during mammary cancer progression. Beginning at 3 or 5 wk of age, spontaneous dwarf rats (Gh(dr/dr)), which lack GH and have very low serum IGF-I, were treated with either rat or bovine GH twice daily. Other Gh(dr/dr) rats received vehicle, and wild-type Sprague Dawley rats (Gh(+/+), parent strain to SDR) received vehicle. One week later, all rats were exposed to a single injection of N-methyl-N-nitrosourea. Body weight gain and serum IGF-I levels were similar in Gh(+/+) and GH-treated Gh(dr/dr) rats. Furthermore, mammary tumor incidence, latency, and multiplicity were similar in Gh(+/+) and GH-treated Gh(dr/dr) rats. Vehicle-treated Gh(dr/dr) rats developed no tumors. Once advanced (> or =1 cm(3)) mammary cancers were established in GH-treated Gh(dr/dr) rats, GH treatments were halted and nearly all tumors regressed completely within 2 wk. Tumor regression was associated with loss of phospho-signal transducer and activator of transcription-3, but not alterations in IGF-I, IGF-I receptor, or GH receptor. These results demonstrate that Gh(dr/dr) rats, which are nearly refractory to mammary carcinogenesis, can be made vulnerable by restoring GH and IGF-I. Furthermore, advanced rat mammary cancers are dependent on GH and/or IGF-I for their survival. Therefore, therapeutics that target either GH or IGF-I may be effective at treating even advanced mammary cancers.
Shen
Qi
Q
Department of Medicinal Chemistry and Pharmacognosy, 833 South Wood Street (MC 781), University of Illinois at Chicago, Chicago, IL 60612, USA.
Lantvit
Daniel D
DD
Lin
Qing
Q
Li
Yongjun
Y
Christov
Konstantin
K
Wang
Zhuohua
Z
Unterman
Terry G
TG
Mehta
Rajendra G
RG
Swanson
Steven M
SM
D000818:Animals; D004198:Disease Susceptibility; D004334:Drug Administration Schedule; D004392:Dwarfism / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013006:Growth Hormone / Q000008:administration & dosage / Q000172:deficiency*; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008770:Methylnitrosourea; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D012074:Remission Induction
C073294:growth hormone, bovine; D007334:Insulin-Like Growth Factor I; D008770:Methylnitrosourea; D013006:Growth Hormone