[Involvement of epidermal growth factor receptor signaling pathway in tamoxifen resistance of MCF-7 cells].
OBJECTIVE
Tamoxifen (TAM) is an important endocrine therapeutic drug used in combined treatment for breast cancer. However the drug resistant effect of TAM has become a major concern in clinical use. Epidermal growth factor receptor (EGFR) is expressed in many tumors and the expression of EGFR in breast cancer tissues is associated with poor prognosis. This study was to investigate EGFR signaling pathway in the drug resistant effect of TAM in breast cancer cells.


METHODS
An estrogen receptor (ER) positive breast cancer cell line, MCF-7 was incubated with TAM (10(-7) mol/L) for up to 6 months to produce drug resistant cells. mRNA and protein expression of EGFR signaling pathway related genes and ER gene was analyzed by fluorescent quantitation reverse transcription-polymerase chain reaction (fqRT-PCR) and Western blot. AG1478, an EGFR inhibitor, was also used to study the drug resistant effect of TAM.


RESULTS
The proliferation of MCF-7 cells was inhibited in the early stage after TAM treatment. However the inhibitory effect vanished after continuous 6-month treatment and the cell proliferation rate returned back to normal. The tolerance of MCF-7 cells to TAM was confirmed by cell growth inhibitory test. In TAM resistant MCF-7 cells, the expression of EGFR mRNA was increased by 4.5 times and the protein expression of EGFR, phosphorylation-extracellular signal-regulated kinase (p-ERK1/2) was also increased dramatically (P<0.05). While ER protein expression remained unchanged. Moreover the drug resistant cells were identified more sensitive to AG1478.


CONCLUSIONS
In endocrine therapy, TAM resistant breast cancer cells are likely to be generated by the activation of EGFR signaling pathway after long-term TAM treatment, and EGFR inhibitors might increase the therapeutic effects in breast cancer treatment.
Zhen
Lin-Lin
LL
Department of General Surgery, The First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210029, P. R. China.
Zhu
Xun
X
Zheng
Wei
W
Wang
Xuan-Yi
XY
Wu
Zheng-Yan
ZY
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D011799:Quinazolines; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D020032:Tyrphostins; D013629:Tamoxifen; C101044:RTKI cpd; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3