ERα directly activated the MDR1 transcription to increase paclitaxel-resistance of ERα-positive breast cancer cells in vitro and in vivo.
Chemotherapy is commonly used to treat early-stage invasive and advanced-stage breast cancer either before or after surgery. Increasing evidence from clinical analysis and in vitro studies has shown that ER-positive breast cancer cells are insensitive to chemotherapy. Complete understanding of how ERα mediates drug resistance is prerequisite to improvement of the chemotherapeutic efficacy. Over-expression of P-glycoprotein (P-gp) encoded by MDR1 gene is one of the major causes of drug resistance. The association between ERα and MDR1 in breast cancer is still unclear and the limited reports are conflict. This study systematically explored intrinsic link between ERα and the P-gp over-expression in paclitaxel-resistant ERα(+) breast cancer cell lines and mouse model in molecular details. Our data showed that ERα activated the MDR1 transcription in MCF-7/PTX breast cancer cells by binding to ERE1/2 and interacting with Sp1 that bridged to the downstream CG-rich element within the MDR1 promoter. Knockdown of MDR1 restrained the effect of ERα in MCF-7 cells and sensitized the cells to paclitaxel. Treatment of ICI 182,780 that selectively suppressed ERα significantly decreased the MDR1 expression and increased the sensitivity of drug resistant breast cancer cells and xenograft tumors to paclitaxel. Our data strongly demonstrated that ERα was able to increase drug resistance of breast cancer cells through activating MDR1 transcription. This novel mechanism provides new insight to how the ERα signaling regulates response of ERα(+) breast tumors to chemotherapy, which may be exploited for developing novel therapeutic strategies for breast cancer in the future.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China; Department of Cell Biology, Nanjing Medical University, Nanjing, China.
Jun-Feng
JF
Shi
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Nan
N
Yang
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China; Department of Cell Biology, Nanjing Medical University, Nanjing, China.
Hai-Jian
HJ
Ding
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Jie-Xin
JX
Zhang
Department of Cell Biology, Nanjing Medical University, Nanjing, China.
Mei-Ling
ML
Hu
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China; Department of Cell Biology, Nanjing Medical University, Nanjing, China.
Yan
Y
Leng
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Xiao
X
Han
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China; Department of Cell Biology, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center, Nanjing Medical University, Nanjing, China. Electronic address: yujiesun@njmu.edu.cn.
Yu-Jie
YJ
Sun
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage*; D014158:Transcription, Genetic
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D017239:Paclitaxel
Breast cancer; Chemotherapy resistance; ERα; MDR1; Paclitaxel