Differential regulation of oestrogen receptor β isoforms by 5′ untranslated regions in cancer

J Cell Mol Med 14(8):2172-2184 (2009) PMID 20920096

Estrogen receptors (ERs) are critical regulators of the behaviour of many cancers. Despite this, the roles and regulation of one of the two known ERs - ERbeta - are poorly understood. This is partly because analyses have been confused by discrepancies between ERbeta expression at mRNA and proteins levels, and because ERbeta is expressed as several functionally distinct isoforms. We investigated human ERbeta 5' untranslated regions (UTRs) and their influences on ERbeta expression and function. We demonstrate that two alternative ERbeta 5'UTRs have potent and differential influences on expression acting at the level of translation. We show that their influences are modulated by cellular context and in carcinogenesis, and demonstrate the contributions of both upstream open reading frames and RNA secondary structure. These regulatory mechanisms offer explanations for the non-concordance of ERbeta mRNA and protein. Importantly, we also demonstrate that 5'UTRs allow the first reported mechanisms for differential regulation of the expression of the ERbeta isoforms 1, 2 and 5, and thereby have critical influences on ERbeta function.