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

Abstract

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.

Fibroblast growth factor 7, secreted by breast fibroblasts, is an interleukin-1beta-induced paracrine growth factor for human breast cells

“…IL-1 was included in this study because previous nuclear run-on and promoter studies on the FGF7 gene indicated that IL-1 can stimulate FGF7 gene transcription , Finch et al 1995b. Moreover, previous studies have demonstrated that IL-1 can induce stromal cells to secrete FGF7 in cornea, skin and endometrium , Finch et al 1995b, Li & Tseng 1997, Weng et al 1997, Li & Rinehart 1998. These findings suggest that IL-1 could also have a role in inducing FGF7 production in breast stromal cells.…”

Induction of Keratinocyte Growth Factor 1 Expression by Lipopolysaccharide Is Regulated by CD-14 and Toll-Like Receptors 2 and 4

“…In contrast, PDTC specifically inhibits NF-B activation by decreasing the release of the IB inhibitory unit from latent NF-B (42). The NF-B signaling pathway does play a role in LPS-mediated effects, and this same pathway is involved in IL-1 induction of KGF-1 expression (23,52,59). Collectively, these data, in conjunction with ours, suggest that LPS induction of KGF-1 expression is mediated through NF-B.…”

Estrogen treatment in vivo increases keratinocyte growth factor expression in the mammary gland

“…Examination of the hormonal regulation of KGF expression has shown that in primate endometrium KGF expression is activated by progesterone (Koji et al 1994, Matsui et al 1997, whereas in cultured human endometrial cells KGF expression could be significantly increased after long-term culture with the non-steroidal estrogen, diethylstilbestrol (Li & Rinehart 1998). Hormonal regulation of KGF expression has been studied in ovarian follicles where estrogen and human chorionic gonadotropin were found to stimulate KGF expression in cultured bovine theca cells (Parrott & Skinner 1998).…”