ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis

Rebecca S. Cook, Joan T. Garrett, Violeta Sánchez, Jamie C. Stanford, Christian Young, Anindita Chakrabarty, Cammie Rinehart, Yixian Zhang, Yaming Wu, Lee Greenberger, Ivan D. Horak, Carlos L. Arteaga

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58 Scopus citations

Abstract

The ErbB receptor family member ErbB3 has been implicated in breast cancer growth, but it has yet to be determined whether its disruption is therapeutically valuable. In a mouse model of mammary carcinoma driven by the polyomavirus middle T (PyVmT) oncogene, the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt as well as tumor cell growth. In this phosphatidylinositol-3 kinase (PI3K)-dependent tumor model, ErbB2 is part of a complex containing PyVmT, p85 (PI3K), and ErbB3, that is disrupted by treatment with lapatinib. Thus, full engagement of PI3K/Akt by ErbB2 in this oncogene-induced mouse tumor model may involve its ability to dimerize with and phosphorylate ErbB3, which itself directly binds PI3K. In this article, we report that ErbB3 is critical for PI3K/Akt-driven tumor formation triggered by the PyVmT oncogene. Tissue-specific, Cre-mediated deletion of ErbB3 reduced Akt phosphorylation, primary tumor growth, and pulmonary metastasis. Furthermore, EZN-3920, a chemically stabilized antisense oligonucleotide that targets the ErbB3 mRNA in vivo, produced similar effects while causing no toxicity in the mouse model. Our findings offer further preclinical evidence that ErbB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling.

Original languageEnglish (US)
Pages (from-to)3941-3951
Number of pages11
JournalCancer Research
Volume71
Issue number11
DOIs
StatePublished - Jun 1 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cook, R. S., Garrett, J. T., Sánchez, V., Stanford, J. C., Young, C., Chakrabarty, A., Rinehart, C., Zhang, Y., Wu, Y., Greenberger, L., Horak, I. D., & Arteaga, C. L. (2011). ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. Cancer Research, 71(11), 3941-3951. https://doi.org/10.1158/0008-5472.CAN-10-3775