Endocrine Abstracts (2009) 20 GH1

The new biology of estrogen signaling

J-Å Gustafsson

Department of Medical Nutrition, Karolinska Institutet, Stockholm, Sweden

Estrogen signaling is mediated by two isoforms of the soluble estrogen receptor (ER), ERα and ERβ. In general, ERα and ERβ appear to have distinct, specific actions, sometimes of antagonistic nature (yin/yang). ERβ is widely distributed and studies on mice with deleted ERβ show phenotypic alterations in many tissues, indicating that ERβ has essential roles in several physiological contexts. In the CNS, ERβ is essential for development of the brain and many aspects of estrogen signaling; in the ovary, ERβ is selectively expressed in the granulosa cells and is important for ovulation; in the lung, deletion of ERβ results in fibrosis and hypoxia; in the immune system ERβ deficiency leads to a syndrome reminiscent of chronic myeloid leukemia; in the bladder, female ERβ KO mice develop interstitial cystitis, probably secondary to disturbances in the immune system; in aging ERβ deleted mice, tumors develop in the prostate, ovaries and female pituitaries. The latter phenotypes reflect an antiproliferative action of ERβ, also seen in cultures of breast, colon and prostate cancer cell lines, where microarray studies have indicated that ERβ downregulates a multitude of genes involved in cell proliferation and, conversely, upregulates many genes with tumor suppressor function. ERβ also upregulates several adhesion proteins, notably E-cadherin, consistent with a role of ERβ in cellular differentiation. Proof of principle for the antiproliferative action ERβ has recently been obtained by the antiproliferative action in prostate gland and human prostatic cancer cell lines of synthetic ERβ specific drugs. Yet other ERβ specific drugs have been shown to ameliorate depression, as assessed in various mouse models. Pain is another possible indication for ERβ drugs; ERβ is involved in development of pain pathways in the spinal cord and ERβ drugs have been reported to increase the pain threshold in rodents. ERβ targeted, tissue specific drugs may soon prove useful against several diseases. This lecture will highlight some recent studies on ERβ in our lab with reference to a few of the themes described.

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