Skip to main content

Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies.

Publication ,  Journal Article
Arora, J; Sauer, SJ; Tarpley, M; Vermeulen, P; Rypens, C; Van Laere, S; Williams, KP; Devi, GR; Dewhirst, MW
Published in: Oncotarget
April 18, 2017

Inflammatory breast cancer (IBC) is one of the most lethal breast cancer variants; with existing therapy, 5-yr survival rate is only 35%. Current barriers to successful treatment of IBC include frequent infiltration and the presence of tumor cell clusters, termed tumor emboli, within the breast parenchyma and lymphatics. Prior studies have identified the role of anti-apoptotic signaling, in particular hyperactivation of NFκB and its target genes, in IBC pathobiology and therapeutic resistance. The objectives of this study were to: (1) determine if IBC tumor emboli express anti-apoptotic proteins and (2) develop a high content, multiparametric assay to assess the morphology of the IBC 3D spheroids and to optimize a high throughput format to screen for compounds that can inhibit the formation of the IBC tumor clusters/embolic structures. Immunohistochemical analysis of IBC patient tumor samples with documented tumor emboli revealed high NFκB (p65) staining along with expression of XIAP, a potent anti-apoptotic protein known to interact with NFκB signaling in enhancing survival of malignant cells. Subsequently, the high content assay developed allowed for simultaneous imaging and morphometric analysis, including count and viability of spheroids derived from SUM149, rSUM149 and SUM190 cells and its application to evaluate XIAP and NFκB inhibitory agents. We demonstrate the efficacy of the off-patent drug disulfiram when chelated with copper, which we had previously reported to inhibit NFκB signaling, was highly effective in disrupting both IBC spheroids and emboli grown in vitro. Taken together, these results identify a high-throughput approach to target tumor spheroid formation for drug discovery. Finally, disulfiram is a safe and approved drug for management of alcohol abuse, warranting its evaluation for repurposing in IBC therapy.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

April 18, 2017

Volume

8

Issue

16

Start / End Page

25848 / 25863

Location

United States

Related Subject Headings

  • X-Linked Inhibitor of Apoptosis Protein
  • Tumor Cells, Cultured
  • Spheroids, Cellular
  • Neoplastic Cells, Circulating
  • NF-kappa B
  • Mitochondria
  • Inflammatory Breast Neoplasms
  • Humans
  • High-Throughput Screening Assays
  • Gene Expression
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Arora, J., Sauer, S. J., Tarpley, M., Vermeulen, P., Rypens, C., Van Laere, S., … Dewhirst, M. W. (2017). Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies. Oncotarget, 8(16), 25848–25863. https://doi.org/10.18632/oncotarget.15667
Arora, Jay, Scott J. Sauer, Michael Tarpley, Peter Vermeulen, Charlotte Rypens, Steven Van Laere, Kevin P. Williams, Gayathri R. Devi, and Mark W. Dewhirst. “Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies.Oncotarget 8, no. 16 (April 18, 2017): 25848–63. https://doi.org/10.18632/oncotarget.15667.
Arora J, Sauer SJ, Tarpley M, Vermeulen P, Rypens C, Van Laere S, Williams KP, Devi GR, Dewhirst MW. Inflammatory breast cancer tumor emboli express high levels of anti-apoptotic proteins: use of a quantitative high content and high-throughput 3D IBC spheroid assay to identify targeting strategies. Oncotarget. 2017 Apr 18;8(16):25848–25863.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

April 18, 2017

Volume

8

Issue

16

Start / End Page

25848 / 25863

Location

United States

Related Subject Headings

  • X-Linked Inhibitor of Apoptosis Protein
  • Tumor Cells, Cultured
  • Spheroids, Cellular
  • Neoplastic Cells, Circulating
  • NF-kappa B
  • Mitochondria
  • Inflammatory Breast Neoplasms
  • Humans
  • High-Throughput Screening Assays
  • Gene Expression