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G-protein coupled estrogen receptor 1 (GPER1 / GPR30) as therapeutic target for triple-negative breast cancers
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Triple-negative breast cancers (TNBCs) lack estrogen receptor α (ERα), progesterone receptor, and do not overexpress human epidermal growth factor receptor 2 (Her-2). They are neither susceptible to endocrine therapy nor to a therapy using the anti-Her-2 antibody, trastuzumab. Therefore, an efficient targeted therapy is warranted.

Triple-negative breast cancers frequently express membrane bound estrogen receptor G-protein coupled estrogen receptor 1 (GPER1) also known as G-protein coupled receptor 30 (GPR30) . GPER1 mediates non-genomic effects of 17β-estradiol. In addition, selective estrogen receptor modulator tamoxifen and complete ERα antagonist fulvestrant bind to GPER1 and induce adverse effects in breast cancer cells.

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Funding:

  • Deutsche Forschungsgemeinschaft (GR 1895/10-1), approved on April 12, 2012 for 2 Years.

  • Deutsche Forschungsgemeinschaft (GR 1895/10-2), approved on February 3, 2015 for 2 Years.

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Estrogen receptor β as therapeutic target for triple-negative breast cancers
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Metastasis to bone is a frequent problem of advanced breast cancer. Particularly TNBCs are considered as very aggressive and have a bad prognosis. We could show, that selective activation of ERβ reduces the metastatic potential of TNBC cells. Since treatment with ERβ agonists reduces breast cancer cell invasion and CXCR4 protein expression, an important pro-metastatic factor, the use ERβ agonists might be a novel anti-metastatic therapeutic approach and should be further explored.

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Mechanisms of anti-estrogen resistance and novel therapeutic strategies in cancer
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About 50-64% of human breast cancers express receptors for GnRH. Direct antiproliferative effects of GnRH analogs on human breast cancer cell lines have been shown. They are at least in part mediated by antagonizing growth promoting effects of estradiol, epidermal growth factor (EGF) or insulin-like growth factor (IGF-1/-II). Pretreatment with GnRH analogs blocked EGF-induced autophosphorylation of EGF receptor and activation of mitogen-activated protein kinase (extracellular-signal-regulated kinase 1/2 (ERK1/2)) in these cells. In sublines of MCF-7 and T47D breast cancer cells, which were developed to be resistant to the anti-estrogen 4OH-tamoxifen, HER-2/p185 was overexpressed. Pretreatment of these cell lines with GnRH analogs completely abolished resistance to 4OH-tamoxifen, assessed by 4OH-tamoxifen-induced apoptosis. GnRH analogs counteract EGF-dependent signal transduction in GnRH receptor-positive human breast cancer cells. Through this mechanism, they probably reverse acquired resistance to 4OH-tamoxifen mediated through overexpression or activation of receptors of the c-erbB family.

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Funding:

  • Deutsche Forschungsgemeinschaft (GU 981/1-1)

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