Monoclonal antibody against the ectodomain of E-cadherin (DECMA-1) suppresses breast carcinogenesis: involvement of the HER/PI3K/Akt/mTOR and IAP pathways.

Abstract

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.

• Authors: Sabine M Brouxhon, Stephanos Kyrkanides, Xiaofei Teng, Veena Raja, M Kerry O'Banion, Robert Clarke, Stephen Byers, Andrew Silberfeld, Carmen Tornos, Li Ma
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 12 Pg. 3234-46 (Jun 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23620408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Cadherins
• Inhibitor of Apoptosis Proteins
• MTOR protein, human
• Receptor, ErbB-2
• Oncogene Protein v-akt
• TOR Serine-Threonine Kinases

Topics

• Antibodies, Monoclonal (administration & dosage)
• Breast Neoplasms (immunology, pathology, therapy)
• Cadherins (antagonists & inhibitors, immunology)
• Carcinogenesis (drug effects, immunology)
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Humans
• Inhibitor of Apoptosis Proteins (biosynthesis)
• MCF-7 Cells
• Oncogene Protein v-akt (biosynthesis)
• Phosphatidylinositol 3-Kinases (biosynthesis)
• Receptor, ErbB-2 (biosynthesis)
• Signal Transduction (drug effects, immunology)
• TOR Serine-Threonine Kinases (biosynthesis)