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Advanced Rat Mammary Cancers Are Growth Hormone Dependent

Departments of Medicinal Chemistry and Pharmacognosy (Q.S., D.D.L., Q.L., Y.L., Z.W., S.M.S.), Surgical Oncology (K.C., S.M.S.), and Medicine (T.G.U.), University of Illinois at Chicago, and Department of Veterans Affairs Jesse Brown Medical Center (T.G.U.), Chicago, Illinois 60612; and Illinois Institute of Technology Research Institute (R.G.M.), Chicago, Illinois 60616

Address all correspondence and requests for reprints to: Steven M. Swanson, Ph.D., Department of Medicinal Chemistry and Pharmacognosy, 833 South Wood Street (MC 781), University of Illinois at Chicago, Chicago, Illinois 60612. E-mail: swanson{at}uic.edu.

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 (1 cm³) 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.

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