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TNK2 preserves EGF receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells.

TNK2 preserves EGF receptor expression on the cell surface and enhances

migration and invasion of human breast cancer cells

Howlin J, Rosenkvist J and Andersson T

Breast Cancer Research, 2008, 10, R36

Many of the current therapeutic strategies in breast cancer concentrate on inhibiting or modulating cancer cell proliferation and apoptosis. Most conventional chemotherapy is believed to act through inhibition of highly proliferative cells via a variety of methods and in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, biological agents target the enhanced growth properties of these cells. However, there is now much interest in strategies to target another property of cancer cells, namely their invasive and migratory potential.

Basal-like breast cancer is characterised by a high degree of invasiveness and lack of expression of oestrogen receptor ???progesterone receptor and HER2. Up to 50% of such breast cancers have high expression of epidermal growth factor receptor (EGFR) and currently clinical trials are assessing the benefit of anti-EGFR therapy in patients with basal-like breast cancer. Apart from being highly proliferative, such breast cancers are also associated with increased invasiveness and metastatic potential mediated by the Rho GTPases such as Cdc42, which drives migration via a non-receptor tyrosine kinase now known as TNK2. The latter can act as an oncogene when overexpressed, and amplification of the TNK2 gene and mRNA correlates with poor prognosis.

The current study further elucidates the role of TNK2 expression in breast cancer by using silencing RNA (siRNA) knockdown to study the effect on cell migration and its relationship to its proposed effector breast cancer anti-oestrogen resistance 1 (BCAR1) using the MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cell lines.

SiRNA knockdown of TNK2 resulted in a less invasive morphological appearance but these changes were not seen when BCAR1 (the proposed downstream effector) was targeted, suggesting that these effects of TNK2 may be independent of the BCAR1 pathway. Indeed the authors showed that TNK2 silencing by siRNA led to significant reduction in cell surface EGFR which in turn led to a decrease in migratory ability. In the wild type of breast cancer cell, TNK2 therefore appears to enhance cell migration via a mechanism of preservation of cell surface EGFR expression. TNK2 would in this case be an attractive target for small molecule inhibition and therapy to reduce migration and invasion of breast cancers, but without effect on proliferation and apoptosis. Clinical trials of such agents will therefore be challenging as standard response criteria in early phase trials (in terms of reduction in tumour size) would not necessarily apply.

Commentary by Peter Barrett-Lee

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Article Details
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Title Annotation:Epidermal growth factor receptors; Tyrosine kinase, non-receptor, 2
Author:Barrett-Lee, Peter
Publication:Advances in Breast Cancer
Article Type:Report
Geographic Code:4EUUK
Date:Jun 1, 2008
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