Epidemiologic studies suggest that the growth hormone/insulin-like growth factor I (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 weeks of age, Spontaneous Dwarf Rats (SDR, 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 two weeks. Tumor regression was associated with loss of phospho-STAT3, 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 upon 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.