Advanced Rat Mammary Cancers Are Growth Hormone Dependent

• Published in: Endocrinology (Philadelphia) 2007-10, Vol.148 (10), p.4536-4544
• Main Authors: Shen, Qi, Lantvit, Daniel D, Lin, Qing, Li, Yongjun, Christov, Konstantin, Wang, Zhuohua, Unterman, Terry G, Mehta, Rajendra G, Swanson, Steven M
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Biological and medical sciences; Body weight; Body weight gain; Cancer; Carcinogenesis; Carcinogens; Disease Susceptibility; Drug Administration Schedule; Dwarfism - blood; Dwarfism - genetics; Dwarfism - metabolism; Dwarfism - physiopathology; Epidemiology; Fundamental and applied biological sciences. Psychology; Growth Hormone - administration & dosage; Growth Hormone - deficiency; Growth hormones; Gynecology. Andrology. Obstetrics; Hormones; Insulin-like growth factor I; Insulin-Like Growth Factor I - deficiency; Insulin-Like Growth Factor I - metabolism; Latency; Mammary gland; Mammary gland diseases; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - pathology; Medical sciences; Methylnitrosourea; N-Methyl-N-nitrosourea; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Receptors; Remission Induction; Tumors; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-0513

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 (Ghdr/dr), which lack GH and have very low serum IGF-I, were treated with either rat or bovine GH twice daily. Other Ghdr/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 Ghdr/dr rats. Furthermore, mammary tumor incidence, latency, and multiplicity were similar in Gh+/+ and GH-treated Ghdr/dr rats. Vehicle-treated Ghdr/dr rats developed no tumors. Once advanced (≥1 cm3) mammary cancers were established in GH-treated Ghdr/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 Ghdr/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.