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 b reast cancers. However, the mechanism or mechanisms by which estrogen acts as a hormonal carcinogen are not well understood. We hypothesize that in re sponse to chronic exposure to estrogens, human endometrial stromal fibrobla sts (ESF) produce factors that facilitate neoplastic transformation in epit helial cells. To test this hypothesis, we assessed the regulation of kerati nocyte growth factor (KGF) mRNA and protein in ESF by interleukin-l (IL-l) and diethylstilbestrol (DES). Short-term treatments with IL-l 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. KG F protein in medium conditioned by ESF chronically treated with 1 nM DES re ached concentrations of approximately 100 ng/mL. At th is concentration, KG F increased endometrial epithelial cell numbers fourfold and enhanced ancho rage independence tenfold. These results suggest that KGF may play a role i n hormonal carcinogenesis by mediating estrogen-induced changes in the inte ractions between stromal and epithelial cells. To address the potential rol e of nuclear transcription factor kappa B (NF-kappa B) in regulating KGF ex pression, we determined the effect of increased expression of its inhibitor , I kappa B alpha, on KGF mRNA and protein levels. Transfection with I kapp a B alpha blocked induction of KGF expression by IL-l but had no effect on the increase in KGF mRNA caused by chronic treatment with DES. These result s suggest that IL-l exerts its effects on KGF by an NF-kappa B-mediated pat hway but that chronic treatment with DES stimulates KGF expression by some other mechanism. (C) 1998 Wiley-Liss, Inc.