Developmental stage determines estrogen receptor alpha expression and non-genomic mechanisms that control IGF-1 signaling and mammary proliferation in mice

• Published in: The Journal of clinical investigation 2012-01, Vol.122 (1), p.192-204
• Main Authors: Tian, Jie, Berton, Thomas R, Shirley, Stephanie H, Lambertz, Isabel, Gimenez-Conti, Irma B, DiGiovanni, John, Korach, Kenneth S, Conti, Claudio J, Fuchs-Young, Robin
• Format: Article
• Language: English
• Subjects: Adapter proteins; Animals; Biomedical research; Breast cancer; Breast Neoplasms - etiology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cattle; Cell cycle; Cell Proliferation; Cyclin D1 - metabolism; Diagnosis; Estradiol - pharmacology; Estrogen; Estrogen Receptor alpha - deficiency; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogens; Female; Gene expression; Gene Expression Regulation, Developmental - drug effects; Genetic aspects; Growth factors; Health aspects; Humans; Insulin Receptor Substrate Proteins - metabolism; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Keratin; Mammary Glands, Animal - cytology; Mammary Glands, Animal - growth & development; Mammary Glands, Animal - metabolism; MAP Kinase Signaling System; Medical prognosis; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Paracrine Communication; Physiological aspects; Physiology; Postmenopausal women; Proto-Oncogene Proteins c-raf - metabolism; Puberty; Receptors; Risk factors; Sexual Maturation; Signal Transduction; Tumorigenesis; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI42204

Insulin like growth factor-1 (IGF-1) stimulates increased proliferation and survival of mammary epithelial cells and also promotes mammary tumorigenesis. To study the effects of IGF-1 on the mammary gland in vivo, we used BK5.IGF-1 transgenic (Tg) mice. In these mice, IGF-1 overexpression is controlled by the bovine keratin 5 promoter and recapitulates the paracrine exposure of breast epithelium to stromal IGF-1 that is seen in women. Studies have shown that BK5.IGF-1 Tg mice are more susceptible to mammary tumorigenesis than wild-type littermates. Investigation of the mechanisms underlying increased mammary cancer risk, reported here, revealed that IGF-1 preferentially activated the PI3K/Akt pathway in glands from prepubertal Tg mice, resulting in increased cyclin D1 expression and hyperplasia. However, in glands from postpubertal Tg mice, a pathway switch occurred and activation of the Ras/Raf/MAPK pathway predominated, without increased cyclin D1 expression or proliferation. We further showed that in prepubertal Tg glands, signaling was mediated by formation of an ERα/IRS-1 complex, which activated IRS-1 and directed signaling via the PI3K/Akt pathway. Conversely, in postpubertal Tg glands, reduced ERα expression failed to stimulate formation of the ERα/IRS-1 complex, allowing signaling to proceed via the alternate Ras/Raf/MAPK pathway. These in vivo data demonstrate that changes in ERα expression at different stages of development direct IGF-1 signaling and the resulting tissue responses. As ERα levels are elevated during the prepubertal and postmenopausal stages, these may represent windows of susceptibility during which increased IGF-1 exposure maximally enhances breast cancer risk.