Progestin suppresses matrix metalloproteinase production in endometrial cancer

Objectives. Endometrial carcinoma (EC) is one of the few cancers where there is a clear relationship between excessive hormone stimulation and malignant transformation. In this study we have analyzed the effects of the female sex steroids estrogen and progesterone on matrix metalloproteinases (MMP-9 and -2) production in primary EC cells and EC cell lines. MMPs are implicated in cancer invasion via mechanisms including extracellular matrix degradation and the processing of a range of molecules, including growth factors and cytokines. Methods. Cells were isolated from biopsies collected from three cancer patients undergoing hysterectomy for grade I endometrial adenocarcinoma and two patients undergoing procedures unrelated to EC. These cells plus the EC cell lines Ishikawa and HEC-1A were cultured without hormones or with medroxyprogesterone acetate (MPA), estradiol (E-2), or these hormones in combination. Gelatin and reverse zymography were used to analyze MMPs and TIMPs, respectively, in culture medium. RT-PCR was used to characterize steroid receptor expression. Results. Cell lines differed from primary cells in the range and abundance of MMPs secreted. Treatment with MPA significantly reduced proMMP-9, proMMP-2, and MMP-2 release from primary EC cancer and stromal cells. Treatment with E-2 alone or MPA + E-2 had no significant effect on MMP expression. Primary EC and stromal cells also showed a loss of the progesterone B receptor isoform. Conclusion. EC cells retain the suppression of MMPs by progesterone, seen in normal endometrial cells. These data provide a rationale for the use of progestin therapy in the treatment of early stage grade I endometrial carcinomas. (C) 2003 Elsevier Science (USA). All rights reserved.