The role of EGF and TGFalpha-EFGR in estrogen effect on endometrial cancinogenesis.

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The in vivo studies demonstrate the EGF is an important autocrine and/or paracrine mediator of estrogen action on uterus. An antibody specific for EGF significantly inhibited estrogen action on uterus. Estrogen induces the expression of TGFalpha mRNA in the mouse uterus in a dose- and time-dependent manner. The up-regulation of TGFalpha transcripts occurs predomonantly in the uterine epithelial cells. RIA and Western blot analysis demonstrate that immunoreactive TGFalpha protein is secreted at high levels into mouse uterine luminal fluid after estrogen treatment. The induction of uterine TGFalpha mRNA is specific to estrogen ; nonestrogenic sterids did not induce expression. Antibody specific to TGFalpha significantly reduces estrogen-mediated uterine growth, which supports the concept that TGFalpha is a mitogen for the reproductive tract. Analysis of TGFalpha/EGF receptor by binding, affinity labeling, and phosphorylation studies indicates that functional receptors are present in the mouse uterus after estrogen exposure. Thus, our data support a physiological role for EGF/TGFalpha and its receptor pathway in the female mouse reproductive tract.