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.

Remifentanil Ameliorates Liver Ischemia-Reperfusion Injury Through Inhibition of Interleukin-18 Signaling

“…23 Protein concentrations were determined with the bicinchroninic acid protein assay kit (Pierce, Rockford, IL). Equal amounts of protein (50 μg) were separated by 8% to 12% Bis-Tris polyacrylamide gel electrophoresis.…”

Insulin-like growth factor — Oestradiol crosstalk and mammary gland tumourigenesis

“…In pre-pubertal animals IGF-1 signalling was dominated by the PI3K/Akt pathway and the presence of an IRS-1/ER complex was clearly identified. In post pubertal animals with lower levels of ER expression no such complex was observed and the main route for signalling proceeded via the Ras/Raf MAPK pathway [88]. Such differences in signalling patterns may differentially affect tumourigenesis during different developmental stages and indicate a potential role for ER in routing IGF signalling pathways.…”

Targeted Genome-Wide Methylation and Gene Expression Analyses Reveal Signaling Pathways Involved in Ovarian Dysfunction after Developmental EDC Exposure in Rats1

“…ESR1 is known to associate with other typical plasma membrane receptors such IGF1R and EGFR and promotes downstream signaling via a kinase cascade activation. One of the most prominent and well-studied of these pathways is the PI3K/Akt signaling pathway [46,47]. Posttranslational modification of mER occurs upon ligand binding followed by localization to the cytoplasm and association with focal adhesion kinase, Src kinase, and the p85 subunit of PI3K [48].…”