title: Combination therapy with anti-DR5 antibody and tamoxifen for triple negative breast cancer.
abstract: TRA-8, a monoclonal antibody targeting death receptor, has demonstrated high therapeutic effect for triple negative breast cancer (TNBC) in preclinical models. Tamoxifen, the standard of care for ERα-positive breast cancer, induces apoptosis via ERβ, which commonly presents in TNBC cells. The current study investigates the combination effects of TRA-8 and tamoxifen for TNBC. In vitro assays were implemented with two ERβ-positive TNBC cell lines, SUM159 and 2LMP, and in vivo therapy studies were followed using orthotopic breast tumor mouse models. IC50 of tamoxifen for SUM159 and 2LMP were 29 μM and 38 μM, respectively. Synergy between TRA-8 (0-1000 ng/mL) and tamoxifen (20 μM) was observed for both the cell lines. Tamoxifen (400 mg/kg diet) markedly suppressed the growth of SUM159 tumors for 6 weeks after therapy initiation, but it did not induce antitumor effect for 2LMP tumors. TRA-8 (0.1 mg, weekly, i.p.) successfully arrested the growth of both SUM159 and 2LMP tumors during therapy, but an antagonistic effect was observed when tamoxifen was combined. TRA-8 uptake into tumors was not changed by tamoxifen treatment. Histological analysis confirmed that caspase-3 activation induced by TRA-8 was significantly decreased when tamoxifen was used in combination. In conclusion, our findings suggest that the combined use of TRA-8 and tamoxifen may cause antagonistic effects for TNBC patients.
authors.affiliation: Department of Radiology; University of Alabama at Birmingham; Birmingham, AL USA; Department of Biomedical Engineering; University of Alabama at Birmingham; Birmingham, AL USA; Comprehensive Cancer Center; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Radiology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Samuel
authors.affiliation: Department of Radiology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Guihua
authors.initials: G
authors.lastname: Zhai
authors.affiliation: Department of Biomedical Sciences; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Rana
authors.affiliation: Department of Radiology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Taylor
authors.affiliation: Department of Radiology; University of Alabama at Birmingham; Birmingham, AL USA; Comprehensive Cancer Center; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Heidi R
authors.initials: HR
authors.lastname: Umphrey
authors.affiliation: Department of Pathology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Denise K
authors.initials: DK
authors.lastname: Oelschlager
authors.affiliation: Comprehensive Cancer Center; University of Alabama at Birmingham; Birmingham, AL USA; Department of Radiation Oncology; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.affiliation: Department of Radiology; University of Alabama at Birmingham; Birmingham, AL USA; Comprehensive Cancer Center; University of Alabama at Birmingham; Birmingham, AL USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008819:Mice, Nude; D055503:Protein Multimerization; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013629:Tamoxifen / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C572208:TRA-8 monoclonal antibody; D013629:Tamoxifen; D053148:Caspase 3
keywords: DWI; TRA-8; fluorescence imaging; precision medicine; predictive biomarker; tamoxifen; triple-negative breast cancer
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