Molecular and Transcriptional Signatures for ErbB2-Induced Invasion

Abstract

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. 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. 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.