Insulin-like growth factors in human breast cancer

Abstract

IGF1 and IGF2 are circulating peptide hormones and locally-acting growth factors with both paracrine and autocrine functions. IGF1 and IGF2 signal through a common tyrosine kinase receptor, the insulin-like growth factor 1 receptor (IGF1R), and have mitogenic, cell survival, and insulin-like actions that are essential for embryogenesis, post-natal growth physiology, and breast development. The activities of IGF1 and 2 are tightly-regulated by a network of binding proteins and targeted degradation mechanisms. This complex regulatory system is disrupted in breast cancer, leading to excess IGF1R signaling. Evidence for this statement includes: a) breast cancers are infiltrated with IGF2 expressing stromal cells; b) mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) is mutated in breast cancer, leading to loss of IGF2 degradation; c) IGF1R is overexpressed by malignant breast epithelial cells, and in some cases IGF1R is amplified; and d) complex changes in IGF binding protein expression occur during breast cancer progression which most likely also affect IGF1 and 2 signaling. The clinical importance of these epigenetic and genetic changes has recently been stressed by the finding that IGF1R signaling alters the apoptotic response of breast cancer cells to genotoxic stress and, in addition, IGF1R activation sensitizes cells to estrogen by inducing phosphorylation of the estrogen receptor. As a consequence of these findings, we propose that IGF analysis of breast cancer samples should shift from prognostic studies to an evaluation of IGF ligands, receptors, and binding proteins as resistance/sensitivity markers for radiation, chemotherapy, and endocrine therapy.

Expression of protein tyrosine phosphatase alpha (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo

“…However, the target of RPTPa in insulin signaling is as yet unknown. Insulin-like growth factors are clearly implicated in progression through the cell cycle, proliferation, and inhibition of apoptosis of breast cancer cells in vitro (Ellis et al, 1998;Werner and Le Roith, 1997). Moreover, ®broblasts lacking the IGF-1 receptor are resistant to transformation by dominant acting oncogenes (Sell et al, 1994).…”

“…In breast cancer, HER2/neu overexpression is an important prognostic indicator, and constitutes a therapeutic target (Ross and Fletcher, 1999), but other receptor tyrosine kinases (RTKs) are also overexpressed (Barker et al, 1995;Ellis et al, 1998;Ghoussoub et al, 1998;Maggiora et al, 1998).…”

Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization

“…IGF-2 Insulin-like growth factor (Peyrat et al, 1988;McCann et al, 1996;Ellis et al, 1998;Rasmussen and Cullen, 1998) +8.4-fold70.32…”

Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors

“…This intricate network has been shown to be altered in many cancers potentially leading to disturbed tyrosine kinase signaling and growth advantages (Ellis et al, 1998). Besides direct disturbances through the IGF pathway some IGFBPs, such as IGFBP-3, can inhibit proliferation in an IGF independent manner (Martin et al, 1999).…”