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

Estrogen actions in target organs are normally mediated via activation of nuclear estrogen receptors (ERs). By using mRNA differential display technique, we show, herein, that estradiol-17 beta (E-2) and its catechol metabolite 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 secreted frizzled related protein-2 (SFRP-2) gene was down-regulated (4-fold). Bip, CalP, and CalM are calcium-binding proteins and implicated in calcium homeostasis, whereas SFRP-2 is a negative regulator of Wnt signaling. Bip and Sik-SP also possess chaperone-like functions, Administration of ICI-182,780 or cycloheximide failed to influence these estrogenic responses, demonstrating that these effects occur independent of ER alpha, ER beta, or protein synthesis. In situ hybridization showed differential cell-specific expression of these genes in wild-type and ER alpha(-/-) uteri, Although progesterone can antagonize or synergize estrogen actions, it had minimal effects on these estrogenic responses. Collectively, the results demonstrate that estrogens have a unique ability to influence specific genes in the uterus not involving classical nuclear ERs.