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Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity

Oncogene volume 23, pages 5161–5174 (2004)Cite this article

Abstract

The present study addresses the effect of targeting type I insulin-like growth factor receptor (IGF-IR) with antisense strategies in in vivo growth of breast cancer cells. Our research was carried out on C4HD tumors from an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in Balb/c mice. We employed two different experimental strategies. With the first one we demonstrated that direct intratumor injection of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODNs) to IGF-IR mRNA resulted in a significant inhibition of C4HD tumor growth. In the second experimental strategy, we assessed the effect of intravenous (i.v.) injection of AS [S]ODN on C4HD tumor growth. This systemic treatment also resulted in significant reduction in tumor growth. The antitumor effect of IGF-IR AS[S]ODNs in both experimental protocols was due to a specific antisense mechanism, since growth inhibition was dose-dependent and no abrogation of tumor proliferation was observed in mice treated with phosphorothioate sense ODNs (S[S]ODNs). In addition, IGF-IR expression was inhibited in tumors from mice receiving AS[S]ODNs, as compared to tumors from control groups. We then investigated signal transduction pathways modulated in vivo by AS[S]ODNs treatment. Tumors from AS[S]ODN-treated mice of both intratumoral and intravenous protocols showed a significant decrease in the degree of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation. Activation of two of the main IGF-IR signaling pathways, phosphatidylinositol 3-kinase (PI-3K)/Akt and p42/p44 mitogen-activated protein kinases (MAPK) was abolished in tumors growing in AS[S]ODN-treated animals. Moreover, ErbB-2 tyrosine phosphorylation was blocked by in vivo administration of AS[S]ODNs. On the other hand, we found no regulation of either progesterone receptor expression or activity by in vivo AS[S]ODNs administration. Our results for the first time demonstrated that breast cancer growth can be inhibited by direct in vivo administration of IGF-IR AS[S]ODNs.

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Acknowledgements

This work was supported by grants from Lilly Centre for Women's Health, Eli Lilly and Company and from the Centro Argentino Brasilero de Biotecnología (CABBIO), both awarded to PV Elizalde, and by grant IDB 802/OC-AR PICT 0503402 from the National Agency of Scientific Promotion of Argentina. We thank N Lope for her expert assistance with animal care and C Lanari for providing the MPA-induced mammary tumor model.

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Authors and Affiliations

  1. Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), CONICET, Obligado 2490, Buenos Aires, 1428, Argentina

    Mariana Salatino, Roxana Schillaci, Cecilia J Proietti, Romina Carnevale, Alfredo A Molinolo, Eduardo H Charreau & Patricia V Elizalde

  2. Servicio de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina

    Isabel Frahm

  3. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), Argentina

    Adolfo Iribarren

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  1. Mariana Salatino
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Correspondence to Patricia V Elizalde.

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Salatino, M., Schillaci, R., Proietti, C. et al. Inhibition of in vivo breast cancer growth by antisense oligodeoxynucleotides to type I insulin-like growth factor receptor mRNA involves inactivation of ErbBs, PI-3K/Akt and p42/p44 MAPK signaling pathways but not modulation of progesterone receptor activity. Oncogene 23, 5161–5174 (2004). https://doi.org/10.1038/sj.onc.1207659

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