The endothelin axis: a novel target for pharmacotherapy of female malignancies.

The endothelin axis (ET axis), comprising the three peptides endothelin (ET)-1, -2, -3 and their receptors ET(A)R and ET(B)R, is expressed in various cells and tissues. The biologically active ET-1 is formed by endothelin-converting enzyme (ECE) from inactive big-ET-1. ET-1 has emerged as an important peptide in a host of biological functions, including development, cellular proliferation, apoptosis and angiogenesis, thereby playing an important physiological and pathophysiological role. As these effects are mediated by ET(A)R, activation of ET(B)R prevents apoptosis, inhibits ECE expression and mediates the clearance of ET-1. Emerging data indicate that the ET axis is involved in tumourigenesis and tumour progression of various cancers. Expression of the ET axis has been demonstrated in a wide range of human tumours. Since most data have been reported for female malignancies, this review will focus on the role of the ET axis in cancers of the ovary, the cervix and the breast. In ovarian cancer, activation of ET(A)R by ET-1 is a key mechanism in the cellular signalling network promoting cancer growth and progression. Similar effects have been shown for cervical and endometrial cancer. In breast cancer, ET-1 via ET(A)R promotes proliferation and invasion, mediates bone metastases and predicts unfavourable response to chemotherapy. The outstanding role of ET-1 and ET(A)R in carcinogenesis and tumour progression has led to an extensive search for interfering agents, resulting in the development of selective ET(A)R antagonists on the one hand and inhibitors of the endothelin-converting enzyme (ECE) on the other. Targeting the ET axis via ET(A)R or ECE blockade seems to be a promising approach in the treatment of female malignancies.