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

Oncogene volume 18, pages 2471–2479 (1999)Cite this article

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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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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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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