Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism (2025)

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Abstract Access options Additional access options: Similar content being viewed by others Increased insulin receptor binding and increased IGF-1 receptor binding are linked with increased growth of L6hIR cell xenografts in vivo Determinants of IGF-II influencing stability, receptor binding and activation Activation of the insulin receptor by insulin-like growth factor 2 References Acknowledgements Author information Authors and Affiliations Rights and permissions About this article Cite this article Keywords This article is cited by Metformin counteracts stimulatory effects induced by insulin in primary breast cancer cells Targeting obesity-related dysfunction in hormonally driven cancers Identification of a novel EphB4 phosphodegron regulated by the autocrine IGFII/IRA axis in malignant mesothelioma IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies

Abstract

IGF-II, produced by breast cancer epithelial and stromal cells, enhances tumor growth by activating the IGF-I receptor (IGF-I-R) via autocrine and paracrine mechanisms. Previously we found that the insulin receptor (IR), which is related to the IGF-I-R, is overexpressed in breast cancer cells. Herein, we find that, in breast cancer the IR is activated by IGF-II. In eight human breast cancer cell lines studied there was high affinity IGF-II binding to the IR, with subsequent IR activation. In these lines, IGF-II had a potency up to 63% that of insulin. In contrast, in non malignant human breast cells, IGF-II was less than 1% potent as insulin. Via activation of the IR tyrosine kinase IGF-II stimulated breast cancer cell growth. Moreover, IGF-II also activated the IR in breast cancer tissue specimens; IGF-II was 10 – 100% as potent as insulin. The IR occurs in two isoforms generated by alternative splicing of exon 11; these isoforms are IR-A (Ex11−) and IR-B (Ex11+). IR-A was predominantly expressed in breast cancer cells and specimens and the potency of IGF-II was correlated to the expression of this isoform (P<0.0001). These data indicate, therefore, that the IR-A, which binds IGF-II with high affinity, is predominantly expressed in breast cancer cells and represents a new autocrine/paracrine loop involved in tumor biology.

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Similar content being viewed by others

Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism (7)

Increased insulin receptor binding and increased IGF-1 receptor binding are linked with increased growth of L6hIR cell xenografts in vivo

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Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism (8)

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Article Open access 18 March 2022

Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism (9)

Activation of the insulin receptor by insulin-like growth factor 2

Article Open access 23 March 2024

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Acknowledgements

This work was supported in part by the Associazione Italiana Ricerca sul Cancro (AIRC Milan, Italy), MURST 60% (Italy), the JA Kerner Foundation, the J Gershow Cancer Fund, and the Ladies Auxiliary of Veterans of Foreign Wars (USA). L Sciacca is recipient of an AIRC fellowship, R Mineo is recipient of a FIRC (Federazione Italiana Ricerca sul Cancro) fellowship.

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Authors and Affiliations

  1. Istituto di Medicina Interna, Malattie Endocrine e del Metabolismo, Università di Catania, Ospedale Garibaldi, 95123 Catania, Italy

    Laura Sciacca,Angela Costantino,Giuseppe Pandini,Rossana Mineo,Francesco Frasca,Pierluigi Scalia,Riccardo Vigneri&Antonino Belfiore

  2. Cattedra di Endocrinologia 1, Università `La Sapienza', Policlinico Umberto I, Roma, 00161, Italy

    Paolo Sbraccia

  3. Division of Diabetes and Endocrine Research, University of California, San Francisco, 94115, California, USA

    Ira D Goldfine

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  1. Laura Sciacca

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  2. Angela Costantino

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  3. Giuseppe Pandini

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  4. Rossana Mineo

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  5. Francesco Frasca

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  7. Paolo Sbraccia

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  8. Ira D Goldfine

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  9. Riccardo Vigneri

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  10. Antonino Belfiore

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Sciacca, L., Costantino, A., Pandini, G. et al. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene 18, 2471–2479 (1999). https://doi.org/10.1038/sj.onc.1202600

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  • DOI: https://doi.org/10.1038/sj.onc.1202600

Keywords

  • insulin receptor
  • IGF-I receptor
  • IGF-I
  • IGF-II
  • breast cancer

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Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism (2025)
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