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Molecular and Transcriptional Signatures for ErbB2-Induced Invasion

  • Kinase Inhibitor (A Minden, Section Editor)
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Abstract

Purpose of Review

Invasion and metastasis are the most fatal activities connected to ErbB2. Current ErbB2-targeting therapies are highly efficient against early stage breast cancer, but often fail to cure the advanced cases. It is estimated that the majority of ErbB2-positive, invasive breast cancers are either intrinsically resistant to the current antibody-based therapy or can develop into resistant disease with high risk of metastasis. Local invasion is a prerequisite for metastatic dissemination. Here, we introduce and summarize the latest mechanistic knowledge of how ErbB2 activation can lead to invasion and spreading of breast cancer cells.

Recent Findings

In this review, we focus on the recent research in the molecular and cellular changes that initiate and maintain ErbB2-induced invasion. These comprise mechanisms that can promote cell migration and those that activate the extracellular degradome, as well as the involvement of lysosomes. We also discuss epithelial-to-mesenchymal transition and circulating tumor cells and what is currently known about their role in invasive, ErbB2-positive breast cancer.

Summary

The activation of invasion in ErbB2-positive breast cancer cells is accomplished by initiation of invasion-promoting transcriptional programs, including activation of transcription factors such as myeloid zinc finger 1 (MZF1) and Ets1 that leads to changes in the expression of genes that can drive and maintain the invasive and metastatic cellular phenotype. Increasing our understanding of the downstream components of the ErbB2 signaling, especially those that regulate its invasive function, can contribute to the development of novel treatments that benefit patients with advanced and therapy-resistant ErbB2-positive breast cancer.

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Funding

The work at the laboratory of TK is supported by the Danish Cancer Society Scientific Committee (KBVU) (R124-A7854-15-S2 and R56-A3108-12-S2), the Danish National Research Foundation (DNRF125), the Novo Nordisk Foundation (NNF15OC0017324), and the Danish Medical Research Council (0602-02386B).

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Authors and Affiliations

  1. Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark

    Siri Amanda Tvingsholm, Ditte Marie Brix & Tuula Kallunki

  2. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Tuula Kallunki

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  1. Siri Amanda Tvingsholm
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  2. Ditte Marie Brix
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  3. Tuula Kallunki
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Correspondence to Tuula Kallunki.

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This article is part of the Topical Collection on Kinase Inhibitor

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Tvingsholm, S.A., Brix, D.M. & Kallunki, T. Molecular and Transcriptional Signatures for ErbB2-Induced Invasion. Curr Pharmacol Rep 5, 43–55 (2019). https://doi.org/10.1007/s40495-018-0146-1

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