PCR DISPLAY IDENTIFIES TAMOXIFEN INDUCTION OF THE NOVEL ANGIOGENIC FACTOR ADRENOMEDULLIN BY A NON ESTROGENIC MECHANISM IN THE HUMAN ENDOMETRIUM

Tamoxifen is currently the most widely used drug for the treatment of breast cancer, but there now exists considerable evidence that tamoxif en can also induce endometrial hyperplasia in pre menopausal women. We have used PCR differential display on primary human endometrial isola tes in an attempt to identify genes induced by but not estrogen. Eight such tamoxifen differentially expressed bands were cloned and sequenc ed, one of which was found to be the peptide adrenomedullin. We have s hown that adrenomedullin is a novel growth factor for endothelial cell s and is angiogenic in vivo in the chick chorioallantoic membrane assa y. Immunohistochemical analysis of endometrial sections have shown tha t while macrophages in the endometrium express adrenomedullin at a low level, endometrial macrophages of women receiving tamoxifen strongly express adrenomedullin (P=0.008). We postulate that endometrial induct ion of the angiogenic factor adrenomedullin by tamoxifen is part of th e mechanism by which tamoxifen results in endometrial hyperplasia.