GnRH-Rezeptor-vermittelte Therapie des triple-negativen Mammakarzinoms

Abstract

Triple-negative breast cancer does not express estrogen and progesterone receptors and there is no overexpression/amplification of the HER2-neu gene. Therefore this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. About 60% of all human breast cancers express GnRH receptors, which might be used as a target. The GnRH receptor can be used for targeted chemotherapy with cytotoxic GnRH agonists such as AN-152, in which doxorubicin is linked to [D-Lys6]GnRH. In the present study I have analyzed in vitro and in vivo whether cytotoxic GnRH agonist AN-152 induces apoptosis in triple-negative human breast cancer cells that express GnRH receptors. GnRH receptor expression in tumor biopsy specimens of triple-negative breast cancers was tested using immune histochemistry. Cell proliferation was analyzed using alamar blue proliferation assay. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human breast tumors. We could show that treatment of triple-negative but GnRH-positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AN-152 resulted in apoptotic cell death in vitro via activation of caspase-3. These antitumor effects could be confirmed in nude mice. AN-152 inhibited the growth of xenotransplants of triple-negative human breast cancers in nude mice completely, without any apparent side effects. Cytotoxic GnRH agonist AN-152 seems to be a suitable drug for an efficacious therapy for triple-negative breast cancers with little toxicity. (Föst C, Duwe F, Hellriegel M, Schweyer S, Emons G, Gründker C (2011). Targeted chemotherapy for triple-negative breast cancers via LHRH receptor. Oncol Rep, 25, 1481-7.)