STAT3-RANTES autocrine signaling is essential for tamoxifen resistance in human breast cancer cells.
The acquisition of tamoxifen resistance is a major therapeutic problem in breast cancer. We developed a tamoxifen-resistant MCF-7 (TRM-7) cell line to elucidate the molecular mechanisms and factors associated with acquisition of such resistance. We showed that phosphorylation of STAT3 at tyrosine 705 (Y705) and RANTES expression are increased in response to tamoxifen in human breast cancer cells. On the basis of these results, we hypothesize that upregulated STAT3 phosphorylation and RANTES may be correlated with the development of drug resistance. Here, we showed that STAT3 and RANTES contribute to the maintenance of drug resistance. STAT3 phosphorylation is constitutively retained via a RANTES autocrine loop, which in turn upregulates anti-apoptotic signals in TRM-7 cells. STAT3-RANTES autocrine signaling affected expression of anti-apoptotic BCL-2 family genes and prevented TRM-7 cells from undergoing programmed cell death by inhibiting PARP and caspase-9 cleavage. Subsequently, blockade of STAT3 and RANTES in TRM-7 cells resulted in reduction of anti-apoptotic signals, which was rescued by exogenous RANTES treatment; drug resistance was also restored. Taken together, our results suggested that STAT3-RANTES autocrine signaling is essential for maintenance of drug resistance and inhibition of programmed cell death. These mechanisms of STAT3-RANTES autocrine signaling suggest a novel strategy for management of patients with tamoxifen-resistant tumors.
Department of Pharmacology, Seoul National University College of Medicine, 103 Daehangno, Jongno-gu, Seoul 110-799, Korea.
Eun Hee
EH
Yi
Chang Seok
CS
Lee
Jin-Ku
JK
Lee
Young Ju
YJ
Lee
Min Kyung
MK
Shin
Chung-Hyun
CH
Cho
Keon Wook
KW
Kang
Jung Weon
JW
Lee
Wonshik
W
Han
Dong-Young
DY
Noh
Yong-Nyun
YN
Kim
Ik-Hyun
IH
Cho
Sang-Kyu
SK
Ye
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013629:Tamoxifen