Der Östrogenrezeptor ERβ unter dem Einfluss selektiver Östrogenrezeptorliganden in kastrationsresistenten Prostatakarzinomzellen

Der Östrogenrezeptor ERβ unter dem Einfluss selektiver Östrogenrezeptorliganden in kastrationsresistenten Prostatakarzinomzellen

The estrogen receptor beta under influence of selective estrogen receptor ligands in castration-resistant prostate cancer cells

Nicole Rudolph

Doctoral thesis

Date of Examination: 2020-06-30

Date of issue: 2020-06-25

Advisor: Trojan, Lutz Prof. Dr.

Referee: Trojan, Lutz Prof. Dr.

Referee: Emons, Günter Prof. Dr.

Persistent Address: http://hdl.handle.net/21.11130/00-1735-0000-0005-13F2-4

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Abstract

English

Prostate cancer can develop to a castration-resistant form during and through a lowering of the androgen level to castration level and can continue to grow. So far, there is no confirmed therapy that can be used successfully from this point. ERβ is an important regulatory tumor suppressor in prostate cancer that is no longer expressed in the CRPC. However, it is possible to increase expression again by stimulating the cells with DPN or 8β-VE2. In the studies of this work, the effects of the genes ARfl and AR-V7, CYP17A and AKR1C3 as well as PSA and TPPRSS2: ERG, which are important in carcinogenesis, were investigated after ERβ stimulation of the CRPC model cell line VCaP. The proliferation of the cells during stimulation was also analyzed. To examine gene expressions, RNA and proteins were analyzed and a BrdU proliferation test was carried out. The effects of the two selective ligands were different. Although both achieved an increase in ERβ expression, stimulation with 8β-VE2 then led to a decrease in the expression of important proto-oncogenes and thus in the direction of inhibition of progression, cell cycle arrest, apoptosis and differentiation of the cells. Stimulation with DPN, on the other hand, resulted in a much lower increase in ERβ expression and only a slight influence on the proto-oncogenes. After 8β-VE2 stimulation, a down-regulation of the ARfl central for the CRPC and its splice variant AR-V7 was shown. There was also a decrease in expression of AR-regulated genes PSA and TMPRSS2-ERG, which is a malignant gene fusion typical of the VCaP cell line. Due to the reduced expression of androgen-regulated genes, altered processes could be observed as counter-regulation in enzymes that are important for androgen synthesis. An increase in CYP17A1 expression and a decrease in AKR1C3 expression were shown to be contradictory regulations.

Keywords: castration-resistant; prostate cancer; estrogen receptor beta; 8β-VE2