Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-alpha activation via the mitogen-activated protein kinase pathway.
BACKGROUND
Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer.


METHODS
Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17beta-estradiol and progesterone. The 17beta-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed.


RESULTS
IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17beta-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the alpha-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-alpha in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D1 and transforming growth factor-beta3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous rats.


CONCLUSIONS
We argue that tumor initiation (transformation and fixation of mutations) may be similar in parous and age-matched virgin animals, suggesting that the main differences in tumor formation lie in differences in tumor progression caused by the altered hormonal environment associated with parity. Furthermore, we provide evidence supporting the notion that tumor growth promotion seen in IGF-I-treated parous rats is caused by activation of estrogen receptor-alpha via the Raf/Ras/mitogen-activated protein kinase cascade.
Thordarson
Gudmundur
G
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, California, USA. gummi@biology.ucsc.edu
Slusher
Nicole
N
Leong
Harriet
H
Ochoa
Dafne
D
Rajkumar
Lakshmanaswamy
L
Guzman
Raphael
R
Nandi
Satyabrata
S
Talamantes
Frank
F
D000230:Adenocarcinoma / Q000139:chemically induced* / Q000517:prevention & control*; D000818:Animals; D044584:Carcinoma, Ductal / Q000139:chemically induced / Q000517:prevention & control; D002291:Carcinoma, Papillary / Q000139:chemically induced / Q000517:prevention & control; D047628:Estrogen Receptor alpha; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000008:administration & dosage / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010298:Parity / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism* / Q000502:physiology
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I; D008770:Methylnitrosourea; D020928:Mitogen-Activated Protein Kinases