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-α activation via the mitogen-activated protein kinase pathway

Autor: Dafne Ochoa, Harriet Leong, Gudmundur Thordarson, Raphael C. Guzman, Frank Talamantes, Nicole Slusher, Satyabrata Nandi, Lakshmanaswamy Rajkumar
Jazyk: angličtina
Rok vydání: 2004
Předmět:
medicine.medical_specialty
endocrine system diseases
medicine.medical_treatment
Mammary gland
mitogen-activated protein kinase progesterone receptor
Estrogen receptor
Tumor initiation
Biology
Adenocarcinoma
Rats
Sprague-Dawley
03 medical and health sciences
Insulin-like growth factor
mammary carcinogenesis
0302 clinical medicine
estrogen receptor-α
Pregnancy
Internal medicine
Progesterone receptor
medicine
Animals
Insulin-Like Growth Factor I
reproductive and urinary physiology
030304 developmental biology
Medicine(all)
growth hormone/insulin-like growth factor-I
0303 health sciences
Mammary tumor
Estrogen Receptor alpha
Mammary Neoplasms
Experimental
Methylnitrosourea
Carcinoma
Papillary
3. Good health
Rats
Carcinoma
Ductal
Parity
Endocrinology
medicine.anatomical_structure
Receptors
Estrogen
030220 oncology & carcinogenesis
Pregnancy
Animal
Female
Mitogen-Activated Protein Kinases
Estrogen receptor alpha
Hormone
Research Article
Zdroj: Breast Cancer Research
ISSN: 1465-542X
1465-5411
Popis: Introduction 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 17β-estradiol and progesterone. The 17β-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 17β-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 α-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-α 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-β3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous rats. Conclusion 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-α via the Raf/Ras/mitogen-activated protein kinase cascade.
Databáze: OpenAIRE
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