Karin Dahlman-Wright

Estrogen signaling in physiology and disease

Our research focuses on the physiological and pathophysiological functions of estrogen signaling and estrogen receptors particularly in relation to metabolic disease and cancer.

Estrogen signaling

As the primary female sex hormone, estrogen promotes the development of female secondary sex characteristics and has traditionally been connected with female reproduction. The importance of this hormone for man and non-reproductive processes, such as metabolism, has been later established. Epidemiological, prospective and experimental studies link estrogen signaling to various cancers including breast cancer and metabolic disease. Most of the known effects of estrogen are mediated via a direct interaction of estrogen with estrogen receptors (ERs), Ealpha and Ebeta, which regulate the expression of specific sets of genes.

Estrogen signaling and metabolic disease

Mice lacking Ealpha mice, EalphaKO, display impaired glucose tolerance (IGT). Insulin resistance observed in these animals is mainly localized to the liver. We have shown that estrogen improves glucose tolerance and insulin sensitivity in diabetic ob/ob mice and high fat diet (HFD) fed mice. Furthermore, treatment of Ob/Ob mice with selective Ealpha agonists improves glucose tolerance, validating the critical role of Ealpha in regulating glucose metabolism. However, the contribution of estrogen signaling in different organs, and how they interact, to determine metabolic phenotypes remain elusive.

Focusing on genes that display consistently differential expression in different animal models we have identified regulation of genes involved in lipid metabolism, and subsequent changes in liver lipid levels, as potential mediators of the effects of estrogen in relation to glucose homeostasis. At the individual gene level, we have identified regulation of stat3, Scd 1 and Lepr as potentially estrogen regulated genes in the liver. Furthermore, it is likely that regulation of glucose production is relevant for the effects of estrogen on glucose tolerance as glucose-6-phosphatase (G6pc) was consistently changed in all models. However, there are differences between the models in how estrogen regulates gene expression and it remains possible that different molecular mechanisms are operating in the different animal models.

Project focus

We are focusing on the molecular mechanism of estrogen signaling in relation to metabolic disease, in particular type 2 diabetes, with the goal to derive novel therapeutic strategies.

• Determine the contribution of estrogen signaling in different organs, and how they interact, to the metabolic phenotypes by studies of mice with eliminated expression of ER{alpha} or ER{beta} in selective tissues.
• Determine the importance of identified gene products and pathways for the effects of estrogen signaling on glucose tolerance.
• Determine the effects of estrogen signaling on metabolites.

Estrogen signaling and breast cancer

Estrogen is essential for growth and development of the mammary glands, and has been associated with promotion and growth of breast cancer. The presence of significant amounts of Ealpha in breast cancer at the time of diagnosis is taken as an indication of hormone dependence, and, on this basis, treatment with anti-estrogens is initiated. However, ER status is not a perfect marker for responsiveness to antiestrogens. Furthermore, resistance to tamoxifen is a serious, and common, clinical problem in the management of breast cancer. Inhibitors of endogeneous estrogen synthesis represent an alternative treatment for breast cancer.

Project Focus

We are focusing on identifying components that modulate estrogen signaling and the gene regulatory networks controlled by estrogen. The goal is to provide novel drug targets and therapeutic opportunities where target estrogen production and/or ER function do not provide sufficient therapeutic effect.

• Identification and modulation of regulators of ER expression with focus on the E3 ubiquitin ligase, RBCK1, that we recently described as a novel regulator of ER{alpha} expression.
• Cross talk between estrogen signaling and other signaling pathways in particular the AP-1 pathway.
• Cross talk between estrogen signaling and epigenetic modifications.
• Estrogen regulation of whole genome transcription and estrogen receptor binding to chromatin.

Some recent publications