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1. Am J Pathol. 2012 Apr 18. [Epub ahead of print]

Increased Expression of P-Glycoprotein and Doxorubicin Chemoresistance of
Metastatic Breast Cancer Is Regulated by miR-298.

Bao L, Hazari S, Mehra S, Kaushal D, Moroz K, Dash S.

Department of Pathology and Laboratory Medicine, Tulane University Health
Sciences Center, New Orleans, Louisiana.

MicroRNAs (miRNAs) are short, noncoding RNA molecules that regulate the
expression of a number of genes involved in cancer; therefore, they offer great
diagnostic and therapeutic targets. We have developed doxorubicin-resistant and
-sensitive metastatic human breast cancer cell lines (MDA-MB-231) to study the
chemoresistant mechanisms regulated by miRNAs. We found that doxorubicin
localized exclusively to the cytoplasm and was unable to reach the nuclei of
resistant tumor cells because of the increased nuclear expression of
MDR1/P-glycoprotein (P-gp). An miRNA array between doxorubicin-sensitive and
-resistant breast cancer cells showed that reduced expression of miR-298 in
doxorubicin-resistant human breast cancer cells was associated with increased
expression of P-gp. In a transient transfection experiment, miR-298 directly
bound to the MDR1 3' untranslated region and regulated the expression of firefly
luciferase reporter in a dose-dependent manner. Overexpression of miR-298
down-regulated P-gp expression, increasing nuclear accumulation of doxorubicin
and cytotoxicity in doxorubicin-resistant breast cancer cells. Furthermore,
down-regulation of miR-298 increased P-gp expression and induced doxorubicin
resistance in sensitive breast cancer cells. In summary, these results suggest
that miR-298 directly modulates P-gp expression and is associated with the
chemoresistant mechanisms of metastatic human breast cancer. Therefore, miR-298
has diagnostic and therapeutic potential for predicting doxorubicin
chemoresistance in human breast cancer.

Copyright © 2012 American Society for Investigative Pathology. Published by
Elsevier Inc. All rights reserved.

PMID: 22521303 [PubMed - as supplied by publisher]