Endothelins in breast tumour cell invasion

Endothelins are a family of small, structurally related, vasoactive peptides that have a great number of physiological roles in many tissues. The 'endothelin axis' consists of three 21 amino acid peptides (ET-1, ET-2 and ET-3), two G-protein-coupled receptors (ET-RA and ET-RB), and two activating peptidases or endothelin-converting enzymes (ECE-1 and ECE-2). There is increased expression of the endothelin axis in invasive breast cancer compared to the normal breast or non-invasive neoplastic tissue. Endothelin expression is associated with invading regions of tumours in patient biopsies and is more common in tumours with high histological grade and lymphovascular invasion, and there is increased systemic endothelin in patients with lymph node metastases compared to those without lymph node involvement. Stimulation of breast tumour cell lines with endothelins leads to an invasive phenotype in vitro. Over-expression of the endothelins and their receptors is insufficient to induce an invasive phenotype in benign cells, yet expression by tumour cells leads to markedly increased invasive ability indicating that endothelins act in concert with other factors--both autocrine and paracrine--including cytokines, matrix metalloproteinases and the activation of tumour-associated macrophages. The association between endothelins, poor prognosis and invasion may mean that the endothelin axis is a valid therapeutic target for the treatment of invasive breast cancer. This review summarises our current knowledge of endothelins in breast cancer invasion and discusses the potential further directions of such research as well as the possibility of anti-endothelin-based therapy of breast cancer.