Developmental stage determines estrogen receptor alpha expression and non-genomic mechanisms that control IGF-1 signaling and mammary proliferation in mice
Jie Tian, … , Claudio J. Conti, Robin Fuchs-Young
Jie Tian, … , Claudio J. Conti, Robin Fuchs-Young
Published December 19, 2011
Citation Information: J Clin Invest. 2012;122(1):192-204. https://doi.org/10.1172/JCI42204.
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Research Article Oncology

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

Abstract

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.

Authors

Jie Tian, Thomas R. Berton, Stephanie H. Shirley, Isabel Lambertz, Irma B. Gimenez-Conti, John DiGiovanni, Kenneth S. Korach, Claudio J. Conti, Robin Fuchs-Young

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Figure 1

Detection of a developmentally dependent IGF-1 signal transduction pathway switch in mammary glands from Tg BK5.IGF-1 mice.

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Detection of a developmentally dependent IGF-1 signal transduction pathw...
Western blot analyses of total and phosphorylated Akt, mTOR, and Erk1/2 in mammary gland extracts from (A) prepubertal or (B) postpubertal BK5.IGF-1 Tg and WT mice, showing increased phosphorylation of Akt and mTOR in prepubertal Tg glands, and increased activation of Erk1/2 and mTOR in postpubertal Tg glands. (C) Immunohistochemical localization of phosphorylated Akt and Erk1/2 in mammary glands from prepubertal and postpubertal WT and Tg mice (original magnification, ×20). Western blot analysis of total and phosphorylated cyclin D1 expression in mammary glands from (D) prepubertal and (E) postpubertal mice, showing reduced phosphorylation of cyclin D1 at Thr286 in mammary glands from prepubertal, but not postpubertal, Tg mice compared with age-matched WT mice. Each lane represents pooled glands from 4–6 mice of the same age and genotype. Representative Western blots from 3 different pools per genotype/age are shown. Graphs present mean ± SD of densitometric analysis of 5–6 different pools/lanes of each genotype and age. *P < 0.05 versus age-matched WT mice, as determined by Student’s t test.