Estrogen‐mediated post transcriptional down‐regulation of P‐glycoprotein in MDR1‐transduced human breast cancer cells

The human multidrug resistance gene 1 (MDR1) encodes the plasma membrane P‐glycoprotein (P‐gp/ABCB1) that functions as an efflux pump for various anticancer agents. We recently reported that estrogens down‐regulate the expression of breast cancer resistance protein (BCRP/ABCG2). In our present study...

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Bibliographic Details
Published in:Cancer science 2006-11, Vol.97 (11), p.1198-1204
Main Authors: Mutoh, Kazuyoshi, Tsukahara, Satomi, Mitsuhashi, Junko, Katayama, Kazuhiro, Sugimoto, Yoshikazu
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents, Phytogenic - pharmacology
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Biological and medical sciences
Biological Transport
Blotting, Western
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cell Line, Tumor
Down-Regulation
Drug Resistance, Neoplasm
Estradiol - pharmacology
Estrogen Receptor alpha - metabolism
Estrogens - pharmacology
Flow Cytometry
Gene Expression Regulation, Neoplastic
General aspects
Genes, MDR - genetics
Humans
Medical sciences
Neoplasms, Hormone-Dependent - drug therapy
Neoplasms, Hormone-Dependent - genetics
Neoplasms, Hormone-Dependent - metabolism
Original
Pharmacology. Drug treatments
Reverse Transcriptase Polymerase Chain Reaction
Tamoxifen - pharmacology
Transduction, Genetic
Tumor Cells, Cultured
Tumors
Vincristine - pharmacology
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Summary:The human multidrug resistance gene 1 (MDR1) encodes the plasma membrane P‐glycoprotein (P‐gp/ABCB1) that functions as an efflux pump for various anticancer agents. We recently reported that estrogens down‐regulate the expression of breast cancer resistance protein (BCRP/ABCG2). In our present study we demonstrate that estrogens also down‐regulate P‐gp expression in the MDR1‐transduced, estrogen receptor α (ER‐α)‐positive human breast cancer cells, MCF‐7/MDR and T‐47D/MDR. The P‐gp expression levels in MCF‐7/MDR cells treated with 100 pM estradiol were found to be 10–20‐fold lower than the levels in these same cells that were cultured without estradiol. In contrast, estradiol did not affect the P‐gp expression levels in the ER‐α‐negative cancer cells, MDA‐MB‐231/MDR and NCI/ADR‐RES. Estrone and diethylstilbestrol were also found to down‐regulate P‐gp in MCF‐7/MDR cells, but progesterone treatment did not produce this effect. Tamoxifen reversed the estradiol‐mediated down‐regulation of P‐gp in MCF‐7/MDR cells, suggesting that ER‐α activity is necessary for the effects of estradiol upon P‐gp. However, estradiol was found not to alter the MDR1 transcript levels in either MCF‐7/MDR and T‐47D/MDR cells, suggesting that post‐transcriptional mechanisms underlie its effects upon P‐gp down‐regulation. MCF‐7/MDR cells also showed eight‐fold higher sensitivity to vincristine when treated with 100 pM estradiol, than when treated with 1 pM estradiol. These results may serve to provide a better understanding of the expression control of ABC transporters, and possibly allow for the establishment of new cancer chemotherapy strategies that would control P‐gp expression in breast cancer cells and thereby increase their sensitivity to MDR1‐related anticancer agents. (Cancer Sci 2006; 97: 1198–1204)
ISSN:1347-9032
1349-7006
DOI:10.1111/j.1349-7006.2006.00300.x