title: Effect of anti-DR5 and chemotherapy on basal-like breast cancer.
abstract: The purpose is to evaluate sensitivity of basal-like breast cancer to treatment with anti-DR5 alone and in combination with chemotherapy. Cytotoxicity of TRA-8 anti-DR5 alone and in combination with doxorubicin or paclitaxel was examined. The role of a DR5-associated molecule (DDX3) in the regulation of apoptosis by recruitment of cIAP1 to the DR5/DDX3 complex was studied. SUM159 and 2LMP orthotopic xenografts were treated with TRA-8 alone and in combination with Abraxane or doxorubicin, and tumor growth inhibition determined. Diffusion-weighted magnetic resonance imaging was used to monitor early tumor response. The majority (12/15) of basal-like cell lines were very sensitive to TRA-8-induced cytotoxicity (IC(50) values of 1.0-49 ng/ml). In contrast, 8/11 luminal or HER2-positive cell lines were resistant (IC(50) > 1,000 ng/ml). Enhanced killing of basal-like cell lines was produced by combination treatment with TRA-8 and doxorubicin. Majority of basal cell lines expressed lower levels of DR5-associated DDX3 and cIAP1 than luminal and HER2-positive cell lines. TRA-8 inhibited growth of basal xenografts and produced 20% complete 2LMP tumor regressions. TRA-8 and chemotherapy produced greater 2LMP growth inhibition than either alone. An increase in apparent diffusion coefficient in 2LMP tumors was measured in a week of therapy with TRA-8 and Abraxane. Basal-like cell lines were more sensitive to TRA-8-mediated cytotoxicity than HER2-over-expressing and luminal cell lines, and chemotherapy enhanced cytotoxicity. High sensitivity of basal cells to TRA-8 correlated with low expression of DR5/DDX3/cIAP1 complex. Treatment with TRA-8 and chemotherapy may be an effective therapy for basal-like breast cancer.
authors: Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.
authors: Patsy G
authors: PG
authors: Oliver
authors: Albert F
authors: AF
authors: LoBuglio
authors: Tong
authors: T
authors: Zhou
authors: Andres
authors: A
authors: Forero
authors: Hyunki
authors: H
authors: Kim
authors: Kurt R
authors: KR
authors: Zinn
authors: Guihua
authors: G
authors: Zhai
authors: Yufeng
authors: Y
authors: Li
authors: Choo H
authors: CH
authors: Lee
authors: Donald J
authors: DJ
authors: Buchsbaum
mesh_terms: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D018295:Neoplasms, Basal Cell / Q000175:diagnosis / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D011485:Protein Binding; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C572208:TRA-8 monoclonal antibody; D004317:Doxorubicin; D053487:DEAD-box RNA Helicases; D017239:Paclitaxel