Expression of nuclear insulin receptor substrate 1 in breast cancer

Abstract

Background: Insulin receptor substrate 1 (IRS-1), a cytoplasmic protein transmitting signals from the insulin and insulin-like growth factor 1 receptors, has been implicated in breast cancer. Previously, it was reported that IRS-1 can be translocated to the nucleus and modulate oestrogen receptor a (ERa) activity in vitro. However, the expression of nuclear IRS-1 in breast cancer biopsy specimens has never been examined. Aims: To assess whether nuclear IRS-1 is present in breast cancer and non-cancer mammary epithelium, and whether it correlates with other markers, especially ERa. Parallel studies were carried out for the expression of cytoplasmatic IRS-1. Methods: IRS-1 and ERa expression was assessed by immunohistochemical analysis. Data were evaluated using Pearson's correlation, linear regression and receiver operating characteristic analysis. Results: Median nuclear IRS-1 expression was found to be low in normal mammary epithelial cells (1.6%) and high in benign tumours (20.5%), ductal grade 2 carcinoma (11.0%) and lobular carcinoma (,30%). Median ERa expression in normal epithelium, benign tumours, ductal cancer grade 2 and 3, and lobular cancer grade 2 and 3 were 10.5, 20.5, 65.0, 0.0, 80 and 15%, respectively. Nuclear IRS-1 and ERa positively correlated in ductal cancer (p,0.001) and benign tumours (p,0.01), but were not associated in lobular cancer and normal mammary epithelium. In ductal carcinoma, both nuclear IRS-1 and ERa negatively correlated with tumour grade, size, mitotic index and lymph node involvement. Cytoplasmic IRS-1 was expressed in all specimens and positively correlated with ERa in ductal cancer. Conclusions: A positive association between nuclear IRS-1 and ERa is a characteristic for ductal breast cancer and marks a more differentiated, non-metastatic phenotype.

Divergent Roles for IRS-1 and IRS-2 in Breast Cancer Metastasis

“…For example, a recent study reported a positive correlation between IRS-1 nuclear expression and a more well-differentiated, non-metastatic phenotype for ductal breast cancer. 74 This finding provides evidence that IRS-1 may have distinct functions that are dependent upon where it is localized within the cell and that the activity of this adaptor protein can be regulated by recruitment to or exclusion from a specific intracellular compartment. An alternative explanation for the conflicting immunohistochemical studies is that IRS-1 may be expressed in tumors with a poor prognosis, is not active.…”

Insulin Receptor Substrate 2-mediated Phosphatidylinositol 3-kinase Signaling Selectively Inhibits Glycogen Synthase Kinase 3β to Regulate Aerobic Glycolysis

“…Both Irs-1 and Irs-2 can recruit and activate PI3K to promote Akt signaling when stimulated with IGF-1, but the functional outcomes that result from this activation are different. Irs-1 and Irs-2 have distinct subcellular localization patterns in human tumors, with Irs-1 localized to both the cytoplasm and nucleus and Irs-2 to the cytoplasm and at the cell membrane (16,17). Irs-2 membrane localization is a predictor of reduced breast cancer patient overall survival, whereas Irs-1 nuclear localization is associated with tumors that are more differentiated and non-metastatic and more sensitive to tamoxifen response (16,18).…”

“…Distinct functions for IRS-1 and IRS-2 in human breast tumors are also indicated by their unique intracellular localization patterns. Tumor cells express both IRS-1 and IRS-2 in the cytoplasm, whereas IRS-1 also localizes to the nucleus and IRS-2 to the cell membrane (16,17). Nuclear localization of IRS-1 correlates with an increased response to tamoxifen and improved patient survival, whereas IRS-2 cell membrane localization correlates with decreased overall patient survival (16,18).…”

The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression

“…1). The expression of IRS1 is increased in breast cancer tissues, with particularly high levels in well-differentiated compared with poorly differentiated tumors (Sisci et al 2007). …”