Progestin suppresses matrix metalloproteinase production in endometrial cancer

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.

Cells were isolated from biopsies collected from three cancer patients undergoing hysterectomy for grade 1 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.

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.

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 1 endometrial carcinomas.