Differential modulation by estradiol of P-glycoprotein drug resistance protein expression in cultured MCF7 and T47D breast cancer cells.
BACKGROUND
Multidrug resistance (MDR) is associated with over expression of the P-glycoprotein (P-gp) drug transporter, which is encoded by the MDR1 gene. Estradiol (E2) is thought to regulate P-gp expression in breast cancer and the aim of this study was to determine the role of estrogen receptor subtypes (ERalpha and ERbeta) in modulating drug resistance and P-gp expression in cultured breast carcinoma cells.


METHODS
The cytotoxic effects of doxorubicin and P-gp concentrations were determined in E2-treated and untreated T47D and MCF7 breast carcinoma cells. Western blot and mobility shift/super shift analyses were used to determine estrogen receptor subtype interaction with AP1 and Sp1 transcription factors.


RESULTS
ERalpha-positive MCF7 cells were resistant to doxorubicin cytotoxicity, while ERbeta-expressing T47D cells were sensitive to doxorubicin treatment. E2 increased the cytoplasmic concentration of P-gp in MCF7 cells but not in T47D cells. ERalpha binds both AP1 and Sp1 transcription factors in extracts from MCF7 cells, while ERbeta binds AP1 in extracts from T47D cells.


CONCLUSIONS
These interactions of the ER subtypes with transcription factors correlates with their functional effects on the MDR1 promoter and the observed effects of E2 on drug resistance.
Zampieri
Luigi
L
Department of Medicine, University of the Witwatersrand Medical School, Parktown, South Africa.
Bianchi
Pepita
P
Ruff
Paul
P
Arbuthnot
Patrick
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000970:Antineoplastic Agents / Q000633:toxicity*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D011033:Podophyllin / Q000031:analogs & derivatives* / Q000378:metabolism; D011034:Podophyllotoxin / Q000031:analogs & derivatives; D011960:Receptors, Estrogen / Q000032:analysis; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D018808:Transcription Factor AP-1; D004958:Estradiol; C003170:mitopodozide; D004317:Doxorubicin; D011033:Podophyllin; D011034:Podophyllotoxin