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The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl.

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Citation: Breast Cancer Research & Treatment. 155(2):235-51, 2016 Jan.PMID: 26759246Institution: Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Antibodies, Monoclonal/pd [Pharmacology] | *Proto-Oncogene Proteins/me [Metabolism] | *Receptor Protein-Tyrosine Kinases/me [Metabolism] | *Receptors, TNF-Related Apoptosis-Inducing Ligand/ag [Agonists] | *Triple Negative Breast Neoplasms/dt [Drug Therapy] | *Vimentin/me [Metabolism] | Apoptosis/de [Drug Effects] | Biomarkers, Tumor/me [Metabolism] | Cell Line, Tumor | Female | Humans | MCF-7 Cells | Receptors, TNF-Related Apoptosis-Inducing Ligand/me [Metabolism] | Triple Negative Breast Neoplasms/me [Metabolism]Year: 2016 ISSN:

0167-6806

Name of journal: Breast cancer research and treatmentAbstract: 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.All authors: Amiri-Kordestani L, Chavez KJ, Conway CM, Dine JL, Greer YE, Hewitt SM, Lipkowitz S, Merchant AS, O'Sullivan CC, Sinclair S, Steinberg SM, Stone B, Swain SM, Voeller DFiscal year: 2016Date added to catalog: 2017-03-06

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Item type	Current library	Collection	Call number	Status	Date due	Barcode
Journal Article	MedStar Authors Catalog	Article	26759246	Available		26759246

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.

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