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


  • 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 ER/IRS-1 complex, which activated IRS-1 and directed signaling via the PI3K/Akt pathway. Conversely, in postpubertal Tg glands, reduced ER expression failed to stimulate formation of the ER/IRS-1 complex, allowing signaling to proceed via the alternate Ras/Raf/MAPK pathway. These in vivo data demonstrate that changes in ER expression at different stages of development direct IGF-1 signaling and the resulting tissue responses. As ER 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.

published proceedings

  • J Clin Invest

altmetric score

  • 3.25

author list (cited authors)

  • Tian, J., Berton, T. R., Shirley, S. H., Lambertz, I., Gimenez-Conti, I. B., DiGiovanni, J., ... Fuchs-Young, R.

citation count

  • 28

complete list of 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

publication date

  • January 2012