Differential Regulation of Growth Factors and Matrix Metalloproteinase-1 by Estrogen, Progesterone, and Tamoxifen in Normal and Cancerous Endometrial cells

AIM: The goal of this research was to determine the effects of estrogen, progesterone, a combination of estrogen and progesterone, and tamoxifen on normal or cancerous endometrial cells with regards to the expression of transforming growth factor-β (TGF-β), epidermal growth factor (EGF), transforming growth factor-α (TGF-α), and matrix metalloproteinase-1 (MMP-1); with implications to mechanisms by which these hormones or anti-estrogen may facilitate or prevent cancer. METHODS: Normal and cancerous endometrial cells, respectively, were exposed to estrogen, progesterone, a combination of estrogen and progesterone or tamoxifen and examined for protein levels of TGF-α, TGF-β, EGF and MMP-1 by ELISA and for transcriptional regulation of MMP-1 by transient transfection of MMP-1 promoterreporter plasmid. RESULTS: Estrogen, progesterone and the combination of these hormones stimulated the expression of TGF-α, TGF-β, EGF and MMP-1 (transcriptionally) in normal endometrial cells. In cancer cells, estrogen stimulated the expression of TGF-α, TGF-β, EGF and MMP-1 (transcriptionally) and the combination of estrogen and progesterone further stimulated the expression of these proteins, whereas progesterone did not have significant effects. Tamoxifen inhibited MMP-1 expression transcriptionally in normal and cancer cells, though to a greater extent in normal cells, without significantly altering the expression of growth factors. CONCLUSION: Estrogen and progesterone similarly stimulate the expression of growth factors and MMP-1 in normal cells whereas progesterone potentiates the effects of estrogen in cancer cells. It suggests that these hormones are detrimental to normal cells as hormone replacement therapy, and facilitate tumorigenesis especially in combination. However, tamoxifen is beneficial to endometrial cells via the inhibition of MMP-1 expression.