title: The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl.
abstract: Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist.
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.|Intramural Research Program, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA.|Sinclair School of Nursing, University of Missouri, Columbia, MO, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dine
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.
authors.forename: Ciara C
authors.initials: CC
authors.lastname: O'Sullivan
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Voeller
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.
authors.forename: Yoshimi E
authors.initials: YE
authors.lastname: Greer
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Chavez
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Conway
authors.affiliation: Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sinclair
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Stone
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.
authors.forename: Laleh
authors.initials: L
authors.lastname: Amiri-Kordestani
authors.affiliation: Center for Cancer Research Bioinformatics Core, Advanced Biomedical Computing Center, SAIC-Frederick, Frederick, MD, USA.
authors.forename: Anand S
authors.initials: AS
authors.lastname: Merchant
authors.affiliation: Sinclair School of Nursing, University of Missouri, Columbia, MO, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Biostatistics & Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, USA.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Swain
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA. lipkowis@mail.nih.gov.
authors.forename: Stanley
authors.initials: S
authors.lastname: Lipkowitz
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D011518:Proto-Oncogene Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D014746:Vimentin; D020794:Receptor Protein-Tyrosine Kinases; C548876:drozitumab; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: Axl; Drozitumab; TRAIL receptor agonists; Triple-negative breast cancer; Vimentin