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

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Mutoh K, Tsukahara S, Mitsuhashi J, Katayama K, Sugimoto Y

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

Cancer Sci. 2006 Nov;97(11):1198-204. Epub 2006 Aug 22.

PubMed ID

16925584 [ View in PubMed

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Abstract

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 alpha (ER-alpha)-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-alpha-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-alpha 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Estradiol	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Downregulator Regulator	Details

Pharmaco-proteomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Diethylstilbestrol	Approved Investigational Withdrawn	ABCB1	5243	decreased	Diethylstilbestrol results in decreased expression of ABCB1 protein	7q21.12
Estrone	Approved	ABCB1	5243	decreased	Estrone results in decreased expression of ABCB1 protein	7q21.12