The Emerging Role of the Fetal Insulin Receptor in Hormone-refractory Breast Cancer

Tanvi Mathur, Douglas Yee

Research output: Contribution to journalArticle


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 (IGF)-I and -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 with 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 1 possible reason for these failures. IR is expressed as 2 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-expresses 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 mediate 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 cotargeting IR-A and IGF-1R could provide a novel, more effective therapy method.

Original languageEnglish (US)
Article numberbqab147
JournalEndocrinology (United States)
Issue number10
StatePublished - Oct 1 2021

Bibliographical note

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© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail:


  • Insulin
  • breast cancer
  • cancer cell stemness
  • insulin receptor
  • insulin-like growth factors
  • type I insulin-like growth factor


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