Insulin Receptor Isoforms in Cancer

Abstract

The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.

Loss of Proprotein Convertase Furin in Mammary Gland Impairs proIGF1R and proIR Processing and Suppresses Tumorigenesis in Triple Negative Breast Cancer

“…Indeed, the importance of Furin processing of various precursors may explain the anti-tumorigenic and anti-metastatic effects of Furin silencing in PyMT;KO mice. Defects in IGF1R or IR expression and/or activation inhibit tumorigenicity, and cause substantial apoptosis in vitro and in vivo [36,37]. This anti-oncogenic effect of IGF1R inactivation was reported to involve the modulation of the levels and activation of various effectors required for tumor growth and survival including AKT and ERK1/2 [38].…”

Diabetes, metformin and cancer risk in myotonic dystrophy type I

“…If validated, this novel observation may help elucidate the pathological mechanisms underlying carcinogenesis in DM1. It is possible that the aberrant expression of the insulin receptor (IR) gene could play a role in cancer development among DM1 patients . Normally, splicing of the IR gene results in two isoforms to which insulin can bind: IR‐A and IR‐B; while all cells express both isoforms, insulin responsive tissue such as adipose, liver and muscle tissue predominately express IR‐B .…”

Diabetes as a Risk Factor for Breast Cancer

“…Similar to IGF-1, insulin is also a mitogen and plays a significant role in breast cancer, and this might be related to underlying insulin resistance [13]. The expression of the insulin receptor is stimulated by insulin in breast cancer cell lines, and overexpression of it can lead to malignant transformation of breast epithelial cells and activation of oncogenes [14].…”

“…Overproduction of insulin-like growth factor receptor (IGFR; as seen in patients with diabetes) and mutations in genes encoding these enzymes are in several types of cancer such as colon, breast, and prostate cancers. IGFR overproduction and mutation have become targets for new therapeutic interventions [13]. Type 2 diabetes affects adipocytokines and inflammatory mediators, which lead to an increased risk of breast cancer in premenopausal women [17].…”