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

  • Breast Cancer Res Treat. 2016 Jan;155(2):235-51. doi: 10.1007/s10549-015-3673-z.
Jennifer L Dine  1  2  3 ,  Ciara C O'Sullivan  1 ,  Donna Voeller  1 ,  Yoshimi E Greer  1 ,  Kathryn J Chavez  1 ,  Catherine M Conway  4 ,  Sarah Sinclair  5 ,  Brandon Stone  1 ,  Laleh Amiri-Kordestani  1 ,  Anand S Merchant  6 ,  Stephen M Hewitt  3 ,  Seth M Steinberg  7 ,  Sandra M Swain  5 ,  Stanley Lipkowitz  8
Affiliations
  • 1. Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA.
  • 2. Intramural Research Program, National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA.
  • 3. Sinclair School of Nursing, University of Missouri, Columbia, MO, USA.
  • 4. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 5. Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, USA.
  • 6. Center for Cancer Research Bioinformatics Core, Advanced Biomedical Computing Center, SAIC-Frederick, Frederick, MD, USA.
  • 7. Biostatistics & Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 8. Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4B54, Bethesda, MD, USA. [email protected].
PMID: 26759246 DOI: 10.1007/s10549-015-3673-z
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.

Keywords
Axl; Drozitumab; TRAIL receptor agonists; Triple-negative breast cancer; Vimentin.
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