The emerging role of the fetal insulin receptor (IR-A) in hormone-refractory breast cancer.

Abstract

The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane tyrosine kinase receptor and a mediator of the biologic effects of insulin-like growth factor-I and -II (IGF-I/II). Inhibitors of IGF-1R signaling were tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target; essentially all IGF-1R inhibitors failed to provide an additional benefit compared to standard-of-care therapy. In this review, we will evaluate the role the insulin receptor (IR) plays in mediating IGF signaling and subsequent metabolic and mitogenic effects as one possible reason for these failures. IR is expressed as two isoforms, with the fetal isoform IR-A derived from alternative splicing and loss of exon 11, the adult isoform (IR-B) includes this exon. Cancer frequently re-express fetal proteins and this appears to be the case in cancer with a re-expression of the fetal isoform and an increased IR-A: IR-B ratio. The biological effects of IR isoform signaling are complex and not completely understood although it has been suggested that IR-A could stimulate mitogenic signaling pathways, play a role in cancer cell stemness, and mediated tolerance to cancer therapies. From a clinical perspective, the IR-A overexpression in cancer may explain why targeting IGF-1R alone was not successful. However, given the predominance of IR-A expression in cancer, it may also be possible to develop isoform specific inhibitors and avoid the metabolic consequences of inhibiting IR-B. If such inhibitors could be developed, then IR-A expression could serve as a predictive biomarker and co-targeting IR-A and IGF-1R could provide a novel, more effective therapy method.