PHYSICOLOGICAL COUPLING OF GROWTH-FACTOR AND STEROID-RECEPTOR SIGNALING PATHWAYS - ESTROGEN-RECEPTOR KNOCKOUT MICE LACK ESTROGEN-LIKE RESPONSE TO EPIDERMAL GROWTH-FACTOR

Past studies have shown that epidermal growth factor (EGF) is able to mimic the uterotropic effects of estrogen in the rodent, These studies have suggested a ''cross-talk'' model in which EGF receptor (EGF-R) s ignaling results in activation of nuclear estrogen receptor (ER) and i ts target genes in an estrogen-independent manner. Furthermore, in vit ro studies have indicated the requirement for ER in this mechanism. To verify the requirement for ER in an in who system, EGF effects were s tudied in the uteri of ER knockout (ERKO) mice, which lack functional ER The EGF-R levels, autophosphorylation, and c-fos induction were obs erved at equivalent levels in both genotypes indicating that removal o f ER did not disrupt the EGF responses. Induction of DNA synthesis and the progesterone receptor gene in the uterus were measured after EGF treatment of both ERKO and wild-type animals, Wild-type mice showed in creases of 4.3-fold in DNA synthesis, as well as an increase in PR mRN A after EGF treatment, However, these responses were absent in ERKO mi ce, confirming that the estrogen-like effects of EGF in the mouse uter us do indeed require the ER These data conclusively demonstrate the co upling of EGF and ER signaling pathways in the rodent reproductive tra ct.