Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency drivermutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell-like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR- 34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c- SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC.
| Original language | English |
|---|---|
| Pages (from-to) | 927-939 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 15 2016 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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MiR-34a silences c-SRC to attenuate tumor growth in triple-negative breast cancer. / Adams, Brian D.; Wali, Vikram B.; Cheng, Christopher J.; Inukai, Sachi; Booth, Carmen J.; Agarwal, Seema; Rimm, David L.; Györffy, Balázs; Santarpia, Libero; Pusztai, Lajos; Saltzman, W. Mark; Slack, Frank J.
In: Cancer Research, Vol. 76, No. 4, 15.02.2016, p. 927-939.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - MiR-34a silences c-SRC to attenuate tumor growth in triple-negative breast cancer
AU - Adams, Brian D.
AU - Wali, Vikram B.
AU - Cheng, Christopher J.
AU - Inukai, Sachi
AU - Booth, Carmen J.
AU - Agarwal, Seema
AU - Rimm, David L.
AU - Györffy, Balázs
AU - Santarpia, Libero
AU - Pusztai, Lajos
AU - Saltzman, W. Mark
AU - Slack, Frank J.
PY - 2016/2/15
Y1 - 2016/2/15
N2 - Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency drivermutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell-like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR- 34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c- SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC.
AB - Triple-negative breast cancer (TNBC) is an aggressive subtype with no clinically proven biologically targeted treatment options. The molecular heterogeneity of TNBC and lack of high frequency drivermutations other than TP53 have hindered the development of new and effective therapies that significantly improve patient outcomes. miRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are becoming promising therapeutic agents. We performed miRNA-profiling studies in different TNBC subtypes to identify miRNAs that significantly contribute to disease progression. We found that miR-34a was lost in TNBC, specifically within mesenchymal and mesenchymal stem cell-like subtypes, whereas expression of miR-34a targets was significantly enriched. Furthermore, restoration of miR-34a in cell lines representing these subtypes inhibited proliferation and invasion, activated senescence, and promoted sensitivity to dasatinib by targeting the proto-oncogene c-SRC. Notably, SRC depletion in TNBC cell lines phenocopied the effects of miR- 34a reintroduction, whereas SRC overexpression rescued the antitumorigenic properties mediated by miR-34a. miR-34a levels also increased when cells were treated with c-SRC inhibitors, suggesting a negative feedback exists between miR-34a and c-SRC. Moreover, miR-34a administration significantly delayed tumor growth of subcutaneously and orthotopically implanted tumors in nude mice, and was accompanied by c- SRC downregulation. Finally, we found that miR-34a and SRC levels were inversely correlated in human tumor specimens. Together, our results demonstrate that miR-34a exerts potent antitumorigenic effects in vitro and in vivo and suggests that miR-34a replacement therapy, which is currently being tested in human clinical trials, represents a promising therapeutic strategy for TNBC.
UR - http://www.scopus.com/inward/record.url?scp=84960378101&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84960378101&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-2321
DO - 10.1158/0008-5472.CAN-15-2321
M3 - Article
AN - SCOPUS:84960378101
VL - 76
SP - 927
EP - 939
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 4
ER -