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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.
- Source :
-
Breast cancer research : BCR [Breast Cancer Res] 2010; Vol. 12 (4), pp. R49. Date of Electronic Publication: 2010 Jul 14. - Publication Year :
- 2010
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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.<br />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.<br />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.<br />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.
- Subjects :
- Animals
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Breast Neoplasms pathology
Caspase 3 metabolism
Cell Line, Tumor
DNA, Antisense genetics
Enzyme Activation drug effects
Female
Gonadotropin-Releasing Hormone antagonists & inhibitors
Gonadotropin-Releasing Hormone genetics
Gonadotropin-Releasing Hormone metabolism
Gonadotropin-Releasing Hormone pharmacology
Humans
Mammary Neoplasms, Experimental metabolism
Mammary Neoplasms, Experimental pathology
Mice
Mice, Nude
Protein Precursors genetics
Protein Precursors metabolism
Receptor, ErbB-2 deficiency
Receptor, ErbB-2 genetics
Receptors, Estrogen deficiency
Receptors, Estrogen genetics
Receptors, Progesterone deficiency
Receptors, Progesterone genetics
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Apoptosis drug effects
Gonadotropin-Releasing Hormone analogs & derivatives
Mammary Neoplasms, Experimental drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1465-542X
- Volume :
- 12
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Breast cancer research : BCR
- Publication Type :
- Academic Journal
- Accession number :
- 20630060
- Full Text :
- https://doi.org/10.1186/bcr2606