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Role of endothelin-2 in breast tumour cell invasion.
Since reports of increased ET-2 expression in human breast cancer (2002), there has been growing interest in ET-2 within cancer pathogenesis. There is increased expression of the ‘endothelin axis’ consisting of 21 amino acid peptides (ET-1, ET-2 and ET-3), two G-protein coupled receptor s and two activating peptidases in invasive breast cancer. This increased expression is not seen in non-invasive tissue. This is further supported by observations from patient biopsies, endothelin expression is associated specifically with regions of the tumour that are invasive and is more common in whole tumours with lymphovascular invasion.

In vitro, when breast tumour cell lines with endothelins are stimulated, the phenotype becomes invasive. Invasion through an artificial membrane can be stimulated, particularly when co-cultured in the presence of macrophages. The association between endothelins, poor prognosis and invasion suggests the endothelin axis is an interesting therapeutic target for the treatment of invasive breast cancer.

The breast tumour microenvironment, particularly a hypoxic microenvironment, modulates the expression of numerous ‘pro-tumour’ genes including endothelins. This hypoxic environment can be created in vitro resulting in increased expression of ET-2 by breast tumour cells. This increased ET-2 expression provides the tumour with autocrine protection from hypoxia-associated apoptosis allowing growth of the tumour. Further research using mice with breast tumours in hypoxic conditions showed that the addition of ET-2 increased the survival of tumour cells suggesting the upregulation of ET-2 in hypoxic tumours may explain the increased invasive potential and worse prognosis than their well oxygenated counterparts.