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Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis

Oncogene volume 31, pages 706–715 (2012)Cite this article

Abstract

Many malignancies show increased expression of the epidermal growth factor (EGF) receptor family member ErbB3 (HER3). ErbB3 binds heregulin β-1 (HRGβ1) and forms a heterodimer with other ErbB family members, such as ErbB2 (HER2) or EGF receptor (EGFR; HER1), enhancing phosphorylation of specific C-terminal tyrosine residues and activation of downstream signaling pathways. ErbB3 contains six YXXM motifs that bind the p85 subunit of phosphoinositide 3 (PI3)-kinase. Previous studies demonstrated that overexpression of ErbB3 in mammary tumor cells can significantly enhance chemotaxis to HRGβ1 and overall metastatic potential. We tested the hypothesis that ErbB3-mediated PI3-kinase signaling is critical for heregulin-induced motility, and therefore crucial for ErbB3-mediated invasion, intravasation and metastasis. The tyrosines in the six YXXM motifs on the ErbB3 C-terminus were replaced with phenylalanine. In contrast to overexpression of the wild-type ErbB3, overexpression of the mutant ErbB3 did not enhance chemotaxis towards HRGβ1 in vitro or in vivo. We also observed reduced tumor cell motility in the primary tumor by multiphoton microscopy, as well as a dramatically reduced ability of these cells to cross the endothelium and intravasate into the circulation. Moreover, whereas mutation of the ErbB3 C-terminus had no effect on tumor growth, it had a dramatic effect on spontaneous metastatic potential. Treatment with the PI3-kinase inhibitor PIK-75 similarly inhibited motility and invasion in vitro and in vivo. Our results indicate that stimulation of the early metastatic steps of motility and invasion by ErbB3 requires activation of the PI3-kinase pathway by the ErbB3 receptor.

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Acknowledgements

We thank John Koland and the members of the Segall, Condeelis, Cox, Hodgson, and Hynes laboratories for comments and suggestions. JES is the Betty and Sheldon Feinberg Senior Faculty Scholar in Cancer Research. This work was supported by grants from the NIH (JES: CA77522 and CA100324); CA1U01105490 and CA100324 (JS Condeelis and J Wyckoff); RO1 GM55692 (JB); NIH P01 CA100324 (JB and ARB).

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Authors and Affiliations

  1. Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    T Smirnova, Z N Zhou, J Wyckoff, P J Boimel, S J Coniglio, J S Condeelis & J E Segall

  2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    R J Flinn & J M Backer

  3. Gruss Lipper Center for Biophotonics, Albert Einstein College of Medicine, Bronx, NY, USA

    J Wyckoff, J S Condeelis & J E Segall

  4. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA

    M Pozzuto & A R Bresnick

  5. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    N E Hynes

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  1. T Smirnova
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Correspondence to J E Segall.

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Smirnova, T., Zhou, Z., Flinn, R. et al. Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis. Oncogene 31, 706–715 (2012). https://doi.org/10.1038/onc.2011.275

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