Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells

Veronica Vella, Marika Giuliano, Alessandro La Ferlita, Michele Pellegrino, Germano Gaudenzi, Salvatore Alaimo, Michele Massimino, Alfredo Pulvirenti, Alessandra Dicitore, Paolo Vigneri, Giovanni Vitale, Roberta Malaguarnera, Andrea Morrione, Andrew H. Sims, Alfredo Ferro, Marcello Maggiolini, Rosamaria Lappano, Ernestina Marianna De Francesco, Antonino Belfiore

Research output: Contribution to journalArticlepeer-review

Abstract

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.
Original languageEnglish
Pages (from-to)3145
JournalCells
Volume10
Issue number11
Early online date12 Nov 2021
DOIs
Publication statusE-pub ahead of print - 12 Nov 2021

Keywords

  • insulin receptor isoform A
  • insulin receptor isoforms
  • IGF axis
  • breast cancer
  • triple negative breast cancer
  • insulin receptor isoform transcriptome
  • tumor promotion
  • hyperinsulinemia

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