ErbB/EGF signaling and EMT in mammary development and breast cancer - PubMed (original) (raw)

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ErbB/EGF signaling and EMT in mammary development and breast cancer

Katharine M Hardy et al. J Mammary Gland Biol Neoplasia. 2010 Jun.

Abstract

Activation of the ErbB family of receptor tyrosine kinases via cognate Epidermal Growth Factor (EGF)-like peptide ligands constitutes a major group of related signaling pathways that control proliferation, survival, angiogenesis and metastasis of breast cancer. In this respect, clinical trials with various ErbB receptor blocking antibodies and specific tyrosine kinase inhibitors have proven to be partially efficacious in the treatment of this heterogeneous disease. Induction of an embryonic program of epithelial-to-mesenchymal transition (EMT) in breast cancer, whereupon epithelial tumor cells convert to a more mesenchymal-like phenotype, facilitates the migration, intravasation, and extravasation of tumor cells during metastasis. Breast cancers which exhibit properties of EMT are highly aggressive and resistant to therapy. Activation of ErbB signaling can regulate EMT-associated invasion and migration in normal and malignant mammary epithelial cells, as well as modulating discrete stages of mammary gland development. The purpose of this review is to summarize current information regarding the role of ErbB signaling in aspects of EMT that influence epithelial cell plasticity during mammary gland development and tumorigenesis. How this information may contribute to the improvement of therapeutic approaches in breast cancer will also be addressed.

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Figure 1

Figure 1

Signaling by epithelial growth factor receptors (ErbBs) has been shown to stimulate epithelial to mesenchymal transition (EMT) in epithelial-like cancer cells by activating different intracellular receptor tyrosine kinases (RTK). This often results in increased activity of transcription factors, such as Snail that represses the expression of intracellular adhesion molecules like E-cadherin. As a consequence, these cells become more spindle-shaped, express mesenchyme associated molecules, such as Vimentin, N-cadherin and certain Metalloproteases (MMPs), and assume increased aggressiveness as they become more migratory and invasive. Inhibitors of ErbB signaling have been able to interfere with the EMT process in certain cancer cells. In select cases, reversal of EMT has resulted in increased efficacy of anti-cancer therapy in otherwise EMT-associated drug resistant cancer cells.

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