Membrane bound estrogen receptor GPR30 as therapeutic target for the triple-negative breast cancer (TNBC)

• Applicant: Professor Dr. Carsten Gründker
• Subject Area: Gynaecology and Obstetrics
• Term: from 2012 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 218493294

TNBCs lack estrogen receptor alpha (ERa), progesterone receptor (PR), and do not overexpress human epidermal growth factor receptor 2 (Her-2). They are neither susceptible to endocrine therapy nor to a therapy using anti-Her-2 antibody trastuzumab. Therefore, an efficient targeted therapy is warranted. TNBCs frequently express membrane bound estrogen receptor G-protein coupled receptor (GPR30). Apart from the classical genomic estrogen signaling via ERa, a non-genomic pathway via GPR30 exists. By transactivation of EGF receptor (EGF-R) GPR30 causes estrogen-induced activation of serum response element (SRE), whereby proliferation is finally promoted. Activation of growth hormone receptor (GH-R) induces expression of GPR30. We have examined two strategies, in order to use GPR30 as therapeutic target for treatment of TNBC. The 1st strategy was direct inhibition of GPR30, the 2nd strategy was inhibition of GPR30 expression using three different ways: 1.) Not only estrogens, but also anti-estrogens promote growth of TNBCs via GPR30. Estriol was proved as an efficient inhibitor of GPR30. GPR30 inhibition led to a clear reduction of stimulation of EGF-R signaling and thus proliferation. However, due to its low solubility Estriol is not applicable as a suitable inhibitor for clinical use. Better GPR30 antagonist should be developed. 2.) Inhibition of EGF-R tyrosine kinase by Gefitinib, activation of tyrosine phosphatase by GnRH analogs as well as inhibition of GH-R led to a clear reduction of GPR30 expression. Our results indicate that combination of inhibition of EGF-R and GH-R appears most promising. We would like to further investigate these strategies, to point out new ways for improvement of TNBC treatment. Moreover our results have to be examined in vivo, in order to prepare clinical studies.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Günter Emons