Elevated STAT3 Signaling-Mediated Upregulation of MMP-2/9 Confers Enhanced Invasion Ability in Multidrug-Resistant Breast Cancer Cells.
The development of multidrug resistance greatly impedes effective cancer therapy. Recent advances in cancer research have demonstrated that acquisition of multidrug resistance by cancer cells is usually accompanied by enhanced cell invasiveness. Several lines of evidence indicated that cross activation of other signaling pathways during development of drug resistance may increase invasive potential of multidrug-resistant (MDR) cancer cells. However, the accurate mechanism of this process is largely undefined. In this study, to better understand the associated molecular pathways responsible for cancer progression induced by drug resistance, a MDR human breast cancer cell line SK-BR-3/EPR with P-glycoprotein overexpression was established using stepwise long-term exposure to increasing concentration of epirubicin. The SK-BR-3/EPR cell line exhibited decreased cell proliferative activity, but enhanced cell invasive capacity. We showed that the expression of metastasis-related matrix metalloproteinase (MMP)-2/9 was elevated in SK-BR-3/EPR cells. Moreover, SK-BR-3/EPR cells showed elevated activation of STAT3. Activation of STAT3 signaling is responsible for enhanced invasiveness of SK-BR-3/EPR cells through upregulation of MMP-2/9. STAT3 is a well-known oncogene and is frequently implicated in tumorigenesis and chemotherapeutic resistance. Our findings augment insight into the mechanism underlying the functional association between MDR and cancer invasiveness.
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. feizhang03@tmu.edu.cn.|Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China. feizhang03@tmu.edu.cn.|Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. feizhang03@tmu.edu.cn.
Fei
F
Zhang
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. wzy7848354@hotmail.com.|Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China. wzy7848354@hotmail.com.|Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. wzy7848354@hotmail.com.
Zhiyong
Z
Wang
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. fanyanling402@163.com.|Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China. fanyanling402@163.com.|Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. fanyanling402@163.com.
Yanling
Y
Fan
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. xq691589132@hotmail.com.|Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China. xq691589132@hotmail.com.|Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. xq691589132@hotmail.com.
Qiao
Q
Xu
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. jiwei217@126.com.|Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China. jiwei217@126.com.|Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. jiwei217@126.com.
Wei
W
Ji
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. tianrants1985@163.com.|Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China. tianrants1985@163.com.|Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. tianrants1985@163.com.
Ran
R
Tian
Public Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China. rniu@tmu.edu.cn.|Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, China. rniu@tmu.edu.cn.|Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. rniu@tmu.edu.cn.
Ruifang
R
Niu
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D050796:STAT3 Transcription Factor; D015251:Epirubicin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
MMP-2; MMP-9; STAT3; breast cancer; invasion; multidrug-resistant (MDR)