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 3

IGF-1 and E2 affect ERα expression in vivo and in vitro.

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IGF-1 and E2 affect ERα expression in vivo and in vitro. (A) Western...
(A) Western blot analysis showing that the expression of ERα is reduced in mammary glands from postpubertal compared with prepubertal mice. ERα levels are further and significantly reduced in glandular extracts from postpubertal Tg mice compared with age-matched WT mice. Graphs present mean ± SD of densitometric analyses of 4 independent experiments, with representative Western blots shown. *P < 0.05 versus prepubertal WT; #P < 0.05 versus prepubertal Tg; †P < 0.05 versus postpubertal WT as determined by Student’s t test. (B) In MCF-7 cells, ERα expression is reduced following 6 hours of treatment with either 10 nmol/l E2 alone or with a combination of 40 ng/ml IGF-1 and 10 nmol/l E2 in SFM. (C) Also in MCF-7 cells, ERα levels are reduced following 24 hours of treatment with E2 and further and significantly reduced by treatment with a combination of E2 and IGF-1. *P < 0.05 versus untreated cells; #P < 0.05 versus IGF-1–treated cells; †P < 0.05 versus E2-treated cells, as determined by Student’s t test.