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 language | English (US) |
|---|---|
| Pages (from-to) | 115-124 |
| Number of pages | 10 |
| Journal | Cancer Letters |
| Volume | 443 |
| DOIs | |
| State | Published - Feb 28 2019 |
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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 journal › Article
}
TY - JOUR
T1 - The membrane tethered matrix metalloproteinase MT1-MMP triggers an outside-in DNA damage response that impacts chemo- and radiotherapy responses of breast cancer
AU - Thakur, Varsha
AU - Zhang, Keman
AU - Savadelis, Alyssa
AU - Zmina, Patrick
AU - Aguila, Brittany
AU - Welford, Scott
AU - Abdul-Karim, Fadi
AU - Bonk, Kristen W.
AU - Keri, Ruth A.
AU - Bedogni, Barbara
PY - 2019/2/28
Y1 - 2019/2/28
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Chemotherapy
KW - DDR
KW - MT1-MMP
KW - Radiotherapy
UR - http://www.scopus.com/inward/record.url?scp=85058187010&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058187010&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2018.11.031
DO - 10.1016/j.canlet.2018.11.031
M3 - Article
VL - 443
SP - 115
EP - 124
JO - Cancer Letters
JF - Cancer Letters
SN - 0304-3835
ER -