Estrogen targets genes involved in protein processing, calcium homeostasis, and Wnt signaling in the mouse uterus independent of estrogen receptor-alpha and -beta

Estrogen actions in target organs are normally mediated via activation of n uclear estrogen receptors (ERs). By using mRNA differential display techniq ue, we show, herein, that estradiol-17 beta (E-2) and its catechol metaboli te 4-hydroxy-E-2 (4OHE(2)) can modulate uterine gene expression in ER alpha (-/-) mice. Whereas administration of E-2 or 4OHE(2) rapidly up-regulated ( 4-8-fold) the expression of immunoglobulin heavy chain binding protein (Bip ), calpactin I (CalP), calmodulin (CalM), and Sih similar protein (Sik-SP) genes in ovariectomized wildtype or ER alpha(-/-) mice, the expression of s ecreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold ). Bip, CalP, and CalM are calcium-binding proteins and implicated in calci um homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bi p and Sik-SP also possess chaperone-like functions, Administration of ICI-1 82,780 or cycloheximide failed to influence these estrogenic responses, dem onstrating that these effects occur independent of ER alpha, ER beta, or pr otein synthesis. In situ hybridization showed differential cell-specific ex pression of these genes in wild-type and ER alpha(-/-) uteri, Although prog esterone can antagonize or synergize estrogen actions, it had minimal effec ts on these estrogenic responses. Collectively, the results demonstrate tha t estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.