Endocrine Abstracts

Estrogen action: two decades of humbling predictions

L Jameson

Northwestern University, Chicago, Illinois, USA.

Biographical Details

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Over the last two decades, our concepts of estrogen action have changed dramatically. From a clinical perspective, recommendations for estrogen replacement therapy have changed from enthusiasm about the benefits of postmenopausal hormone replacement to recognition that long-term estrogen treatment is associated with increased risk of cardiovascular disease, breast cancer, and uterine cancer. From a basic science perspective, the cloning of the estrogen receptor (ER) provided new insights into how estrogen acts by regulating gene expression. However, our understanding of estrogen action is evolving. Initially, estrogen action focused on a classical signalling model in which ER binds to consensus estrogen response elements (EREs) in DNA and recruited transcriptional co-activators. More recently, a multitude of cellular signalling systems, including tethered transcription pathways whereby ER interacts with other transcription factors, growth factor signalling convergence with estrogen receptor action, and membrane-initiated estrogen signalling have been recognized as important components of estrogen action. This lecture will focus on insights gleaned from studies of a Nonclassical Estrogen Receptor Knock In (NERKI) mouse model. In this model, a mutant ERα that is unable to bind to an ERE, but retains intact tethered transcriptional activity, is used to distinguish ERE and non-ERE pathways. By transferring the NERKI ERα allele onto an ERα knockout (ERαKO) genetic background, it is possible to selectively restore non-ERE aspects of ERα signaling. Comparison of the NERKI/ERαKO to the homozygous ERαKO animals allows identification of the in vivo roles of the non-ERE ERα signaling pathways. As an example, selectively restoring non-ERE ERα signaling suppresses serum LH, indicating that the non-ERE pathway is sufficient to mediate a significant component of estrogen negative feedback regulation of LH. We conclude that non-ERE signalling pathways represent an important aspect of estrogen signalling.

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Endocrine Abstracts (2009) 19 S3