27 - 30 May 2005

OESTROGEN-RECEPTOR DEPENDENT GENOMIC RESPONSES OF THE UTERUS Sylvia C. Hewitt [1], Bonnie Deroo [1], Jennifer Collins [2] , Sherry Grissom [2] and Kenneth S Korach [1] [1] Receptor Biology Laboratory of Reproductive and Developmental Toxicology [2] Microarray Group National Institute of Environmental Health Sciences Research Triangle Park North Carolina USA

The mouse uterus is a well-characterised model in which physiological responses to oestrogen have been studied. The uterus expresses high levels of the nuclear oestrogen receptor alpa (ER-alpha), which mediates gene transcriptional responses to estrogens. A second ER, ER-beta, is not readily detected in mouse uterine tissues. Accumulated data has shown that acute estrogen treatment of ovariectomised mice leads to an ordered array of biological responses, with distinct events occurring early (in the first few hours) culminating with a later wave of epithelial cell mitosis (16-24 hours). With the development of the ER-alpha ablated mouse (alpha-ERKO) we were able to show that these responses require ER-alpha.

Microarray analysis of gene changes in uterine tissues has further allowed us to identify genes, both up- and down regulated, that are characteristic of early and late responses. Comparisons of genomic responses in mice lacking ER-alpha or ER-beta have indicated a requirement for ER-alpha. We now are able use this model to study the role of ER in genomic responses of different oestrogenic compounds and correlate them with biological effects. For example, our previous studies have shown that either EGF or IGF-1 can initiate the estrogen-like response of epithelial proliferation in the uterus, and that this response to growth factors did not occur in the alpha-ERKO.

By comparing the genomic responses to oestrogen and growth factors we observed that despite the lack of epithelial proliferation, alpha-ERKO uterine genes mounted a robust response to growth factors. In addition, the genomic profile of other genetically altered strains can be compared to indicate their uterine responsiveness and the role of other genes in establishing uterine function. These studies have indicated the complexity of endogenous uterine gene regulation.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract