Targeted chemotherapy for triple-negative breast cancers via LHRH receptor

被引:45
作者
Foest, Crispin [1 ]
Duwe, Francesca [1 ]
Hellriegel, Martin [1 ]
Schweyer, Stefan [2 ]
Emons, Guenter [1 ]
Gruendker, Carsten [1 ]
机构
[1] Univ Gottingen, Dept Gynecol & Obstet, D-37075 Gottingen, Germany
[2] Univ Gottingen, Dept Pathol, D-37075 Gottingen, Germany
关键词
luteinizing hormone releasing hormone receptor; targeted therapy; AN-152; triple-negative breast cancer; HORMONE-RELEASING HORMONE; HIGH-AFFINITY BINDING; BASAL-LIKE SUBTYPE; GNRH ANTAGONISTS; HUMAN ENDOMETRIAL; HUMAN OVARIAN; CYTOTOXIC ANALOG; AGONISTS; AN-152; EXPRESSION;
D O I
10.3892/or.2011.1188
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Triple-negative breast cancer does not express estrogen and progesterone receptors and there is no over-expression/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 receptors for luteinizing hormone releasing hormone (LHRH, GnRH), which might be used as a target. The LHRH receptor can be used for targeted chemotherapy with eytotoxic luteinizing hormone releasing hormone, agonists such as AEZS-108 (AN-152), in which doxorubicin is linked to [D-Lys(6)]LHRH. In the present study we have analyzed by in vitro and in vivo experiments whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in triple-negative human breast cancer cells that express LHRH receptors. LHRH receptor expression in tumor biopsy specimens of triple-negative breast cancers was tested using immunohistochemistry. Cell proliferation was analyzed using alamar blue proliferation assay. Induction of apoptosis was quantified by measurement of loss of mitochondria] membrane potential. In vivo experiments were performed using nude mice bearing xenografted human breast tumors. Thirty-one of 42 triple-negative breast cancers (73.8%) expressed LHRH receptors. We could show that treatment of triple-negative but LHRH-positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro via activation of caspase-3. The antitumor effects were confirmed in nude mice. AEZS-108 (AN-I 52) inhibited the growth of xenotransplants of triple-negative human breast cancers in nude mice completely, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for an efficacious therapy for triple-negative breast cancers with little toxicity.
引用
收藏
页码:1481 / 1487
页数:7
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