G-protein coupled estrogen receptor 1 (GPER1 / GPR30) as therapeutic target for triple-negative breast cancers
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.
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
Estrogen receptor β as therapeutic target for triple-negative breast cancers
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.
Mechanisms of anti-estrogen resistance and novel therapeutic strategies in cancer
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.
Günthert AR, Gründker
C, Olota A, Läsche J, Eicke N, Emons G (2005) Analogs of gonadotropin-releasing hormone
I (GnRH-I) and GnRH-II inhibit EGF-induced signal transduction and resensitize resistant
human breast cancer cells to 4OH-tamoxifen. European Journal of Endocrinology 153:613-625
Block M, Fister S, Emons
G, Seeber S, Gründker C, Günthert AR (2010) Antiproliferative effects of antiestrogens
and inhibitors of growth factor receptor signaling on endometrial cancer. Anticancer
Block M, Gründker C, Fister S, Kubin J,
Wilkens L, Mueller MD, Hemmerlein B, Emons G, Günthert AR (2012)
Inhibition of the AKT/mTOR and erbB pathways by gefitinib, perifosine
and analogs of gonadotropin-releasing hormone I and II to overcome
tamoxifen resistance in breast cancer cells. International Journal of Oncology 41:1845-1854