Monoclonal Antibody against the Ectodomain of E-Cadherin (DECMA-1) Suppresses Breast Carcinogenesis: Involvement of the HER/PI3K/Akt/mTOR and IAP Pathways

被引:38
作者
Brouxhon, Sabine M. [1 ]
Kyrkanides, Stephanos [2 ]
Teng, Xiaofei [2 ]
Raja, Veena [2 ]
O'Banion, M. Kerry [4 ]
Clarke, Robert [5 ]
Byers, Stephen [5 ]
Silberfeld, Andrew [1 ]
Tornos, Carmen [3 ]
Ma, Li [2 ]
机构
[1] SUNY Stony Brook, Sch Med, Dept Emergency Med, Stony Brook, NY 11794 USA
[2] SUNY Stony Brook, Hlth Sci Ctr, Stony Brook, NY 11794 USA
[3] SUNY Stony Brook, Dept Pathol, Stony Brook, NY 11794 USA
[4] Univ Rochester, Sch Med & Dent, Dept Neurobiol & Anat, Rochester, NY 14642 USA
[5] Georgetown Univ, Sch Med, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC USA
关键词
GROWTH-FACTOR-RECEPTOR; SOLUBLE E-CADHERIN; CELL-CELL ADHESION; CANCER-CELLS; TRASTUZUMAB RESISTANCE; TARGETED THERAPIES; DOWN-REGULATION; UP-REGULATION; BETA-CATENIN; SURVIVAL;
D O I
10.1158/1078-0432.CCR-12-2747
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Although targeted therapies against HER2 have been one of the most successful therapeutic strategies for breast cancer, patients eventually developed acquired resistance from compensatory upregulation of alternate HERs and mitogen-activated protein kinase-phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling. As we and others have shown that the soluble ectodomain fragment of E-cadherin exerts prooncogenic effects via HER1/2-mediated binding and activation of downstream prosurvival pathways, we explored whether targeting this ectodomain [DECMA-1 monoclonal antibody (mAb)] was effective in the treatment of HER2-positive (HER2(+)) breast cancers. Experimental Design: MMTV-PyMT transgenic mice and HER2(+)/E-cadherin-positive MCF-7 and BT474 trastuzumab-resistant (TtzmR) cells were treated with the DECMA-1 mAb. Antitumor responses were assessed by bromodeoxyuridine incorporation, apoptosis, and necrosis. The underlying intracellular prooncogenic pathways were explored using subcellular fractionation, immunoprecipitation, fluorescence microscopy, and immunoblotting. Results: Treatment with DECMA-1 mAb significantly delayed tumor onset and attenuated tumor burden in MMTV-PyMT mice by reducing tumor cell proliferation and inducing apoptosis without any detectable cytotoxicity to mice or end-organs. In vitro treatment of MCF-7 and BT474 TtzmR cells reduced proliferation and induced cancer cell apoptosis. Importantly, this inhibition of breast tumorigenesis was due to concomitant downregulation, via ubiquitin-mediated degradation through the lysosome and proteasome pathways, of all HER family members, components of downstream PI3K/Akt/mTOR prosurvival signaling and suppression of inhibitor of apoptosis proteins. Conclusions: Our results establish that the E-cadherin ectodomain-specific mAb DECMA-1 inhibits Ecad(+)/HER2(+) breast cancers by hindering tumor growth and inducing apoptosis via downregulation of key oncogenic pathways involved in trastuzumab resistance, thereby establishing a novel therapeutic platform for the treatment of HER2(+) breast cancers. (C)2013 AACR.
引用
收藏
页码:3234 / 3246
页数:13
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