Src inhibitor dasatinib inhibits growth of breast cancer cells by modulating EGFR signaling.
EGF-receptor family members (EGFRs) as well as c-Src are over expressed in approximately 70% of breast cancer, and in most of the tumors c-Src is co-over expressed with at least one of the EGFRs, suggesting that they may interact functionally and play a role in the development and progression of the malignancy. We hypothesize that a small molecule inhibitor of c-Src dasatinib (BMS-354825; Bristol Myers Squibb), exerts its effects on breast cancer cells by modulating EGFR signaling. Indeed, we found that dasatinib causes inhibition of breast cancer cells overexpressing EGFR, HER-2 and HER-3 (MDA-MB-468, SKBR3, MDA-MB-453, and MDA-MB-231) in a dose and time-dependent manner. Dasatinib also stimulated apoptosis in MDA-MB-468 cells, which could be attributed to activation of both caspase-9 and -8 and arrest of the cell cycle at G0/G1 cycle. Furthermore, dasatinib markedly inhibited colony formation, cell invasion, migration and angiogenesis, accompanied by decreased phosphorylation of EGFR and c-Src and their downstream effector molecules Akt and Erks. Our data suggest that dasatinib mediates its action in part through EGFR signaling and could be a potential therapeutic agent for breast cancer.
Nautiyal
Jyoti
J
Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, USA.
Majumder
Pralay
P
Patel
Bhaumik B
BB
Lee
Francis Y
FY
Majumdar
Adhip P N
AP
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D066246:ErbB Receptors; D019061:src-Family Kinases; D000069439:Dasatinib