Gonadotropin-releasing hormone type II antagonist induces apoptosis in MCF-7 and triple-negative MDA-MB-231 human breast cancer cells in vitro and in vivo.

Abstract

INTRODUCTION:

Triple-negative breast cancer does not express estrogen and progesterone receptors, and no overexpression/amplification of the HER2-neu gene occurs. Therefore, this subtype of breast cancer lacks the benefits of specific therapies that target these receptors. Today chemotherapy is the only systematic therapy for patients with triple-negative breast cancer. About 50% to 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 showed that antagonists of gonadotropin-releasing hormone type 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 mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK), followed by activation of proapoptotic protein Bax, loss of mitochondrial membrane potential, and activation of caspase-3. In the present study, we 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 ascertained whether knockdown of GnRH-I receptor expression affects GnRH-II antagonist-induced apoptosis and apoptotic signaling.

METHODS:

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

RESULTS:

We showed that treatment of MCF-7 and triple-negative MDA-MB-231 human breast cancer cells with a GnRH-II antagonist results in apoptotic cell death in vitro via activation of stress-activated MAPK p38 and loss of mitochondrial membrane potential. In addition, we showed GnRH-II antagonist-induced activation of caspase-3 in MDA-MB-231 human breast cancer cells. After knockdown 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.

CONCLUSIONS:

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

• Authors: Carsten Gründker, Crispin Föst, Stefanie Fister, Nadine Nolte, Andreas R Günthert, Günter Emons
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 12 Issue 4 Pg. R49 ( 2010) ISSN: 1465-542X [Electronic] England
• PMID: 20630060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Antisense
• GnRH-II, Ac-2-Nal(1)-4Cpa(2)-3Pal(3,6)-Leu(8)-Ala(10)-
• Protein Precursors
• Receptors, Estrogen
• Receptors, Progesterone
• progonadoliberin I
• Gonadotropin-Releasing Hormone
• LHRH, His(5)-Trp(7)-Tyr(8)-
• Receptor, ErbB-2
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• DNA, Antisense (genetics)
• Enzyme Activation (drug effects)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, antagonists & inhibitors, genetics, metabolism, pharmacology)
• Humans
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Protein Precursors (genetics, metabolism)
• Receptor, ErbB-2 (deficiency, genetics)
• Receptors, Estrogen (deficiency, genetics)
• Receptors, Progesterone (deficiency, genetics)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays