Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy.
J Biol Chem
; 290(24): 14811-25, 2015 Jun 12.
Article
in En
| MEDLINE
| ID: mdl-25897074
ABSTRACT
Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast cancer are more resistant to chemotherapy than PTCs because of potentiated DNA repair. Surprisingly, the chemoresistance of CTCs was recapitulated in PTCs when they were detached from the extracellular matrix. Detachment of PTCs increased the levels of reactive oxygen species and partially activated the DNA damage checkpoint, converting PTCs to a CTC-like state. Inhibition of checkpoint kinases Chk1 and Chk2 in CTCs reduces the basal checkpoint response and sensitizes CTCs to DNA damage in vitro and in mouse xenografts. Our results suggest that DNA damage checkpoint inhibitors may benefit the chemotherapy of breast cancer patients by suppressing the chemoresistance of CTCs and reducing the risk of cancer metastasis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Damage
/
Breast Neoplasms
/
Neoplastic Cells, Circulating
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Adult
/
Female
/
Humans
/
Middle aged
Language:
En
Journal:
J Biol Chem
Year:
2015
Document type:
Article