Regulation of keratinocyte growth factor expression in human endometrium: implications for hormonal carcinogenesis

Estrogen is thought to be an important etiologic agent in endometrial and breast cancers. However, the mechanism or mechanisms by which estrogen acts as a hormonal carcinogen are not well understood. We hypothesize that in response to chronic exposure to estrogens, human endometrial stromal fibroblasts (ESF) produce factors that facilitate neoplastic transformation in epithelial cells. To test this hypothesis, we assessed the regulation of keratinocyte growth factor (KGF) mRNA and protein in ESF by interleukin-1 (IL-1) and diethylstilbestrol (DES). Short-term treatments with IL-1 but not with DES increased the abundance of KGF mRNA in ESF. However, chronic treatment with DES significantly increased KGF mRNA levels and protein production. KGF protein in medium conditioned by ESF chronically treated with 1 nM DES reached concentrations of approximately 100 ng/mL. At this concentration, KGF increased endometrial epithelial cell numbers fourfold and enhanced anchorage independence tenfold. These results suggest that KGF may play a role in hormonal carcinogenesis by mediating estrogen-induced changes in the interactions between stromal and epithelial cells. To address the potential role of nuclear transcription factor kappa B (NF-kappaB) in regulating KGF expression, we determined the effect of increased expression of its inhibitor, IkappaBalpha, on KGF mRNA and protein levels. Transfection with IkappaBalpha blocked induction of KGF expression by IL-1 but had no effect on the increase in KGF mRNA caused by chronic treatment with DES. These results suggest that IL-1 exerts its effects on KGF by an NF-kappaB-mediated pathway but that chronic treatment with DES stimulates KGF expression by some other mechanism.