A Phosphotyrosine Switch in Estrogen Receptor ß Is Required for Mouse Ovarian Function.

ABSTRACT

The two homologous estrogen receptors ERα and ERß exert distinct effects on their cognate tissues. Previous work from our laboratory identified an ERß-specific phosphotyrosine residue that regulates ERß transcriptional activity and antitumor function in breast cancer cells. To determine the physiological role of the ERß phosphotyrosine residue in normal tissue development and function, we investigated a mutant mouse model (Y55F) whereby this particular tyrosine residue in endogenous mouse ERß is mutated to phenylalanine. While grossly indistinguishable from their wild-type littermates, mutant female mice displayed reduced fertility, decreased ovarian follicular cell proliferation, and lower progesterone levels. Moreover, mutant ERß from female mice during superovulation is defective in activating promoters of its target genes in ovarian tissues. Thus, our findings provide compelling genetic and molecular evidence for a role of isotype-specific ERß phosphorylation in mouse ovarian development and function.