Role of estrogen receptor beta in mouse prostate and bladder with references to human diseases

After the discovery of estrogen receptor beta (ERbeta) in 1995, it became clear that in many non-classical estrogen-responsive organs, were in fact direct targets for estrogen. One of these organs is prostate gland, where ERbeta is abundant in epithelium. Creation of a mouse with inactivated ERbeta (ERbeta-/- mouse) was indispensable for dissecting the role of ERbeta in different organs. Studies in this thesis focus on the ventral prostate and urinary bladder of ERbeta-/-mice.

Our studies with the ventral prostate showed that ERbeta has an antiproliferative and pro-differentiative role in epithelium and in ERbeta-/- mice there is accumulation of incompletely differentiated so-called intermediate cells. Comparison of the protein expression profiles between ERbeta-/- mice and their wild-type littermates showed dysregulation of several proteins, associated with differentiation. One of the proteins which was over-expressed is the serine protease inhibitor (SPINK). The human counterpart of SPINK is tumor associated trypsin inhibitor (TATI), a known tumor marker for prostate adenocarcinoma. In paraffin embedded section of human prostate, we found that in cancers with low differentiation grade (high Gleason score), ERbeta is downregulated with concomitant upregulation of TATI. Unlike the prostate, in the urinary bladder ERbeta is expressed in the basal cell layer not in the differentiated epithelium and the epithelium of the urinary bladder is fully differentiated. Despite this, in female ERbeta-/- mice there are changes resembling human interstitial cystitis. We found that the most likely cause of urothelial destruction is massive infiltration of urothelium with macrophages and gammadeltaT-cells. We concluded that altered ERbeta signaling in the immune system is the cause of urothelial destruction.

One of the nagging issues in the study of ERbeta has been the identity of the natural ligand for this receptor in the prostate. There is evidence that the most abundant estrogenic steroid in the prostate is 5alpha-androstane-3beta, 17beta-diol (3beta-Adiol), a metabolite of 5alpha-dihydrotestosterone (DHT). We were puzzled over this because blockers of the conversion of testosterone (T) to DHT, 5alpha-reductase inhibitors, are used in the treatment of BPH and have been tested for prevention of prostate cancer. We speculated that 5alpha-reductase inhibitors would lead to a less well differentiated prostatic epithelium. We tested this idea in mice and found that blocking 5alpha-reductase type 2 (SRD5A2) results in altered differentiation of mouse ventral prostate epithelium, similar to what is seen in ERbeta-/- mice. This alteration could be prevented by treatment with ERbeta specific agonist, DPN.

The studies in this thesis lead to the conclusion that ERbeta-selective modulators could be of benefit in the treatment and/or prevention of prostate cancer and interstitial cystitis.

List of scientific papers

I. Imamov O, Morani A, Shim GJ, Omoto Y, Thulin-Andersson C, Warner M, Gustafsson JA (2004). "Estrogen receptor beta regulates epithelial cellular differentiation in the mouse ventral prostate." Proc Natl Acad Sci U S A 101(25): 9375-80. Epub 2004 Jun 8
https://pubmed.ncbi.nlm.nih.gov/15187231

II. Schwend T, Imamov O, Williams C, Ruppert T, Waage L, Bergerheim U, Oschepkov B, Warner M, Gustafsson JÅ (2007). "Serine protease inhibitor Kazal type 3, a marker for poorly differentiated prostatic epithelium in ER beta -/- mice and in prostate cancer." Cancer Research (Submitted)

III. Imamov O, Morani A, Lewandowski S, Schwend T, Svechnikov K, Warner M, Söder O, Gustafsson JÅ (2007). "Blocking of 5 alpha-reductase type 2 alters differentiation of prostatic epithelium due to inhibition of ER beta signaling." (Submitted)

IV. Imamov O, Yakimchuk K, Morani A, Schwend T, Wada-Hiraike O, Razumov S, Warner M, Gustafsson JA (2007). "Estrogen receptor beta-deficient female mice develop a bladder phenotype resembling human interstitial cystitis." Proc Natl Acad Sci U S A 104(23): 9806-9. Epub 2007 May 23
https://pubmed.ncbi.nlm.nih.gov/17522255