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

Kazuyoshi Mutoh, Satomi Tsukahara, Junko Mitsuhashi, Kazuhiro Katayama, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)1198-1204
Number of pages7
JournalCancer Science
Volume97
Issue number11
DOIs
Publication statusPublished - 2006 Nov

Fingerprint

MDR Genes
P-Glycoprotein
Estradiol
Estrogens
Down-Regulation
Breast Neoplasms
MCF-7 Cells
Antineoplastic Agents
Diethylstilbestrol
ATP-Binding Cassette Transporters
Estrone
Vincristine
Tamoxifen
Estrogen Receptors
Progesterone
Cultured Cells
Neoplasms
Cell Membrane
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Estrogen-mediated post transcriptional down-regulation of P-glycoprotein in MDR1-transduced human breast cancer cells. / Mutoh, Kazuyoshi; Tsukahara, Satomi; Mitsuhashi, Junko; Katayama, Kazuhiro; Sugimoto, Yoshikazu.

In: Cancer Science, Vol. 97, No. 11, 11.2006, p. 1198-1204.

Research output: Contribution to journalArticle

Mutoh, Kazuyoshi ; Tsukahara, Satomi ; Mitsuhashi, Junko ; Katayama, Kazuhiro ; Sugimoto, Yoshikazu. / Estrogen-mediated post transcriptional down-regulation of P-glycoprotein in MDR1-transduced human breast cancer cells. In: Cancer Science. 2006 ; Vol. 97, No. 11. pp. 1198-1204.
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