The membrane tethered matrix metalloproteinase MT1-MMP triggers an outside-in DNA damage response that impacts chemo- and radiotherapy responses of breast cancer

Varsha Thakur, Keman Zhang, Alyssa Savadelis, Patrick Zmina, Brittany Aguila, Scott Welford, Fadi Abdul-Karim, Kristen W. Bonk, Ruth A. Keri, Barbara Bedogni

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Breast cancer is the second leading cause of death among women in the US. Targeted therapies exist, however resistance is common and patients resort to chemotherapy. Chemotherapy is also a main treatment for triple negative breast cancer (TNBC) patients; while radiation is delivered to patients with advanced disease to counteract metastasis. Yet, resistance to both chemo- and radiotherapy is still frequent, highlighting a need to provide novel sensitizers. We discovered that MT1-MMP modulates DNA damage responses (DDR) in breast cancer. MT1-MMP expression inversely correlates to chemotherapy response of breast cancer patients. Inhibition of MT1-MMP sensitizes TNBC cells to IR and doxorubicin in vitro, and in vivo in an orthotopic breast cancer model. Specifically, depletion of MT1-MMP causes stalling of replication forks and Double Strand Breaks (DBSs), leading to increased sensitivity to additional genotoxic stresses. These effects are mediated by integrinβ1, as a constitutive active integrinβ1 reverts replication defects and protects cells depleted of MT1-MMP from IR and chemotherapy. These data highlight a novel DNA damage response triggered by MT1-MMP-integrinβ1 and provide a new point of therapeutic targeting that may improve breast cancer patient outcomes.

Original languageEnglish (US)
Pages (from-to)115-124
Number of pages10
JournalCancer Letters
Volume443
DOIs
StatePublished - Feb 28 2019

Fingerprint

Matrix Metalloproteinase 14
Matrix Metalloproteinases
DNA Damage
Radiotherapy
Breast Neoplasms
Drug Therapy
Membranes
Triple Negative Breast Neoplasms
Doxorubicin
Cause of Death
Therapeutics
Radiation
Neoplasm Metastasis

Keywords

  • Breast cancer
  • Chemotherapy
  • DDR
  • MT1-MMP
  • Radiotherapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The membrane tethered matrix metalloproteinase MT1-MMP triggers an outside-in DNA damage response that impacts chemo- and radiotherapy responses of breast cancer. / Thakur, Varsha; Zhang, Keman; Savadelis, Alyssa; Zmina, Patrick; Aguila, Brittany; Welford, Scott; Abdul-Karim, Fadi; Bonk, Kristen W.; Keri, Ruth A.; Bedogni, Barbara.

In: Cancer Letters, Vol. 443, 28.02.2019, p. 115-124.

Research output: Contribution to journalArticle

Thakur, Varsha ; Zhang, Keman ; Savadelis, Alyssa ; Zmina, Patrick ; Aguila, Brittany ; Welford, Scott ; Abdul-Karim, Fadi ; Bonk, Kristen W. ; Keri, Ruth A. ; Bedogni, Barbara. / The membrane tethered matrix metalloproteinase MT1-MMP triggers an outside-in DNA damage response that impacts chemo- and radiotherapy responses of breast cancer. In: Cancer Letters. 2019 ; Vol. 443. pp. 115-124.
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