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Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer.

Publication ,  Journal Article
Drain, AP; Zahir, N; Northey, JJ; Zhang, H; Huang, P-J; Maller, O; Lakins, JN; Yu, X; Leight, JL; Alston-Mills, BP; Hwang, ES; Chen, Y-Y ...
Published in: J Exp Med
May 3, 2021

Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.

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Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

May 3, 2021

Volume

218

Issue

5

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Triple Negative Breast Neoplasms
  • Neoadjuvant Therapy
  • NF-kappa B
  • Mice, SCID
  • Mice, Nude
  • Mice, Inbred NOD
  • Mice
  • JNK Mitogen-Activated Protein Kinases
 

Citation

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ICMJE
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Drain, A. P., Zahir, N., Northey, J. J., Zhang, H., Huang, P.-J., Maller, O., … Weaver, V. M. (2021). Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer. J Exp Med, 218(5). https://doi.org/10.1084/jem.20191360
Drain, Allison P., Nastaran Zahir, Jason J. Northey, Hui Zhang, Po-Jui Huang, Ori Maller, Johnathon N. Lakins, et al. “Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer.J Exp Med 218, no. 5 (May 3, 2021). https://doi.org/10.1084/jem.20191360.
Drain AP, Zahir N, Northey JJ, Zhang H, Huang P-J, Maller O, et al. Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer. J Exp Med. 2021 May 3;218(5).
Drain, Allison P., et al. “Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer.J Exp Med, vol. 218, no. 5, May 2021. Pubmed, doi:10.1084/jem.20191360.
Drain AP, Zahir N, Northey JJ, Zhang H, Huang P-J, Maller O, Lakins JN, Yu X, Leight JL, Alston-Mills BP, Hwang ES, Chen Y-Y, Park CC, Weaver VM. Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer. J Exp Med. 2021 May 3;218(5).

Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

May 3, 2021

Volume

218

Issue

5

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Triple Negative Breast Neoplasms
  • Neoadjuvant Therapy
  • NF-kappa B
  • Mice, SCID
  • Mice, Nude
  • Mice, Inbred NOD
  • Mice
  • JNK Mitogen-Activated Protein Kinases