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Mammary glands reconstituted with Neu/ErbB2 transformed HC11 cells provide a novel orthotopic tumor model for testing anti-cancer agents

Oncogene volume 20, pages 5459–5465 (2001)Cite this article

Abstract

The ErbB2 receptor tyrosine kinase (RTK) has been intensely pursued as a cancer therapy target due to its association with breast cancer. In this study we used the HC11 mammary epithelial cell line to develop an orthotopic, ErbB2-driven tumor model for testing efficacy of anti-cancer compounds. HC11 cells were infected with a retrovirus encoding oncogenic NeuT, the rat homolog of ErbB2. Drug-selected populations were introduced into mammary fat pads of Balb/c syngeneic mice cleared of host tissue. The majority of glands injected with HC11-NeuT cells developed mammary tumors which appeared after a 3–4 week latency period and grew rapidly. HC11 cells infected with the control retrovirus showed no tumor growth after injection. Tumor-bearing mice were used to compare the in vivo efficacy of two anti-cancer agents: PKI166, a kinase inhibitor selective for EGF receptor and ErbB2, and Taxol®, a microtubule assembly blocker. PKI166 inhibited NeuT-induced mammary tumor growth in a dose-dependent manner and at a dose below the maximum tolerated dose (MTD) was significantly more inhibitory than Taxol® at its MTD (57% vs 25% tumor regression). Importantly, there was a dose-dependent decrease in the phosphotyrosine content of NeuT isolated from PKI166-treated, tumor-bearing mice, providing a mechanistic link between kinase inhibition and its anti-tumor activity. Thus, implantation of genetically manipulated HC11 cells into mammary glands appears to be an excellent model for studying effects of anti-cancer agents in an orthotopic site.

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Acknowledgements

We kindly acknowledge the expert technical assistance of F Wenger, L Martinuzzi and W Tinetto. We thank Dr DR Roth for providing information on the tumors from PKI166-treated mice, Dr D Fabbro for the data ErbB kinase inhibition, Dr U Junker and T Bürge for performing the histological analysis, Dr J Mestan for the G410 antibody, and Dr A Racine for the statistical analysis. We appreciate the helpful discussions with Drs T O'Reilly, A Badache, N Li and T Holbro. The laboratory of N.E.H. is supported by the Novartis Research Foundation.

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  1. Friedrich Miescher Institute, P.O. Box 2543, Basel, CH-4002, Switzerland

    Agnes M-L Wong & Nancy E Hynes

  2. Novartis Pharma AG, Oncology/Dept. of in vivo Pharmacology, WLK 125.142, Basel, CH-4002, Switzerland

    Ralf Brandt

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  1. Ralf Brandt
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Correspondence to Nancy E Hynes.

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Brandt, R., Wong, AL. & Hynes, N. Mammary glands reconstituted with Neu/ErbB2 transformed HC11 cells provide a novel orthotopic tumor model for testing anti-cancer agents. Oncogene 20, 5459–5465 (2001). https://doi.org/10.1038/sj.onc.1204709

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