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. Today chemotherapy is the only systematic therapy for patients with triple-negative breast cancer. About 50-64% of human breast cancers express receptors for gonadotropin releasing hormone (GnRH), which might be used as a target. New targeted therapies are warranted. Recently we could show that antagonists of gonadotropin releasing hormone typ II (GnRH-II) induce apoptosis in human endometrial and ovarian cancer cells in vitro and in vivo. This was mediated through activation of stress-induced MAPKs p38 and JNK followed by activation of pro-apoptotic protein Bax, loss of mitochondrial membrane potential and activation of caspase-3. In the present study we have analyzed whether GnRH-II antagonists induce apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells that express GnRH receptors. In addition we have ascertained whether knock-down of GnRH-I receptor expression affects GnRH-II antagonist-induced apoptosis and apoptotic signaling.

Induction of apoptosis was analyzed by measurement of loss of mitochondrial membrane potential. Apoptotic signaling was measured by quantification of activated MAPK p38 and caspase-3 using the western blot technique. GnRH-I receptor protein expression was inhibited using the antisense knock-down technique. In vivo experiments were performed using nude mice bearing xenografted human breast tumors.

We could show that treatment of MCF-7 and triple-negative MDA-MB-231 human breast cancer cells with a GnRH-II antagonist resulted in apoptotic cell death in vitro via activation of stress activated MAPK p38 and loss of mitochondrial membrane potential. In addition, we could show GnRH-II antagonist-induced activation of caspase-3 in MDA-MB-231 human breast cancer cells. After knock-down of GnRH-I receptor expression GnRH-II antagonist-induced apoptosis and apoptotic signaling was only slightly reduced, indicating that an additional pathway mediating the effects of GnRH-II antagonists may exist. The GnRH-I receptor seems not to be the only target of GnRH-II antagonists. The antitumor effects of the GnRH-II antagonist could be confirmed in nude mice. The GnRH-II antagonist inhibited the growth of xenotransplants of human breast cancers in nude mice completely, without any apparent side effects.

GnRH-II antagonists seem to be suitable drugs for an efficacious and less toxic endocrine therapy for breast cancers including triple-negative breast cancers.

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