Rationale and preclinical efficacy of a novel anti-EMP2 antibody for the treatment of invasive breast cancer.
Despite significant advances in biology and medicine, the incidence and mortality due to breast cancer worldwide is still unacceptably high. Thus, there is an urgent need to discover new molecular targets. In this article, we show evidence for a novel target in human breast cancer, the tetraspan protein epithelial membrane protein-2 (EMP2). Using tissue tumor arrays, protein expression of EMP2 was measured and found to be minimal in normal mammary tissue, but it was upregulated in 63% of invasive breast cancer tumors and in 73% of triple-negative tumors tested. To test the hypothesis that EMP2 may be a suitable target for therapy, we constructed a fully human immunoglobulin G1 (IgG1) antibody specific for a conserved domain of human and murine EMP2. Treatment of breast cancer cells with the anti-EMP2 IgG1 significantly inhibited EMP2-mediated signaling, blocked FAK/Src signaling, inhibited invasion, and promoted apoptosis in vitro. In both human xenograft and syngeneic metastatic tumor monotherapy models, anti-EMP2 IgG1 retarded tumor growth without detectable systemic toxicity. This antitumor effect was, in part, attributable to a potent antibody-dependent cell-mediated cytotoxicity response as well as direct cytotoxicity induced by the monoclonal antibody. Together, these results identify EMP2 as a novel therapeutic target for invasive breast cancer.
Authors' Affiliations: Departments of Pathology and Laboratory Medicine, Surgery, Division of Surgical Oncology, Ophthalmology, and Microbiology, Immunology, and Molecular Genetics, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA; Department of Surgery, Greater Los Angeles Veterans Affairs Healthcare System; Department of Pathology, Charles Drew University, Los Angeles, California; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; and Institute of Experimental Biology and Medicine, University of Buenos Aires, Buenos Aires, Argentina.
Maoyong
M
Fu
Erin L
EL
Maresh
Gustavo F
GF
Helguera
Meagan
M
Kiyohara
Yu
Y
Qin
Negin
N
Ashki
Tracy R
TR
Daniels-Wells
Najib
N
Aziz
Lynn K
LK
Gordon
Jonathan
J
Braun
Yahya
Y
Elshimali
Robert A
RA
Soslow
Manuel L
ML
Penichet
Lee
L
Goodglick
Madhuri
M
Wadehra
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects; D046888:Tissue Array Analysis; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C486403:EMP2 protein, human; D008562:Membrane Glycoproteins