In endometrial cancer, loss of progesterone receptors (PR) is associated with more advanced disease. This project aims to investigate the mechanism of action of progesterone and the loss of its receptors (PRA and PRB) in development of endometrial cancer. A 9600-cDNA microarray analysis was performed to study regulation of gene expression in the human endometrial cancer sub-cell line Ishikawa PRAB-36 by the progestagen medroxy progesterone acetate (MPA). Five MPA-regulated genes were selected for further investigation. Expression of these genes was studied by Northern blot and by immunohistochemistry in Ishikawa sub-cell lines expressing different PR isoforms. Additionally, endometrial cancer tissue samples were immunohistochemically stained to study the in vivo protein expression of the selected genes. In the PRAB-36 cell line, MPA was found to regulate the expression of a number of invasion- and metastasis-related genes. Upon further investigation of five of these genes (CD44, CSPG/Versican, Tenascin-C, Fibronectin-1, Integrin-b1), it was observed that expression and progesterone regulation of expression of these genes varied in sub-cell lines expressing different PR isoforms. Furthermore, in advanced endometrial cancer, it was shown that loss of expression of both PR and E-cadherin was associated with increased expression of CD44 and CSPG/Versican . The present study shows that progestagens exert a modulatory effect on the expression of genes involved in tumor cell invasion. As a consequence, loss of PR expression in human endometrial cancer may lead to development of a more invasive phenotype of the respective tumor.