Beeinflusst der knockdown des membranständigen Östrogenrezeptors GPER (GPR30) die anti-invasive Wirksamkeit selektiver Östrogenrezeptor beta (ERb)-Agonisten?

by Vivien Schmitz
Doctoral thesis
Date of Examination:2023-03-21
Date of issue:2023-03-13
Advisor:Prof. Dr. Carsten Gründker
Referee:Prof. Dr. Carsten Gründker
Referee:PD Dr. Silke Kaulfuß
Persistent Address: http://dx.doi.org/10.53846/goediss-9785

 

 

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Abstract

English

The aim of the present work was to investigate to what extent suppression of GPER1 affects viability and invasiveness of TNBC cells. In addition, it was of interest to determine whether suppression of GPER1 affects the efficacy of selective ERβ agonists. In malignant breast cancer cells, estrogen receptor beta (ERb) has anti-proliferative and anti-invasive effects. Accordingly, a significantly better survival of patients with ERb positive triple-negative breast cancer (TNBC) compared to ERb negative TNBC can be achieved. G protein-coupled estrogen receptor 1 (GPER1) is often over-expressed in triple negative breast cancer (TNBC). GPER1 is responsible for many of the non-genomic, membrane-initiated effects of estrogens. Therefore, we have analyzed the effects of GPER1 knockdown using specific siRNA. Transient GPER1 silencing was conducted using RNA interference and confirmed by RT-PCR and western blot. Cell invasion was analyzed by assessment of cell migration rate through an artificial basement membrane in a modified Boyden chamber. Viability of both cell lines was slightly decreased after suppression of GPER1 expression. Knockdown of GPER1 resulted in a significantly reduced invasion of the TNBC cells. The anti-invasive effect of selective ERβ agonists was significantly stronger after knockdown of GPER1 expression. Suppression of GPER1 reduced the metastatic behavior of TNBC cells, improved the anti-invasive efficacy of selective ERβ agonists and plays a significant role in treatment of resistance of breast cancer cells to 4OH-tamoxifen. GPER1 antagonists are considered a possible therapeutic option for TNBC. ERb not only serves as a prognostic marker but represents also a possible target for the therapy of TNBC.
Keywords: GPER1; triple negative breast cancer; selective ERb agonists; invasion; knockdown