| Autor: |
Thomas S; Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America., Thurn KT, Raha P, Chen S, Munster PN |
| Jazyk: |
angličtina |
| Zdroj: |
PloS one [PLoS One] 2013 Jul 09; Vol. 8 (7), pp. e68973. Date of Electronic Publication: 2013 Jul 09 (Print Publication: 2013). |
| DOI: |
10.1371/journal.pone.0068973 |
| Abstrakt: |
Hormonal therapy resistance remains a considerable barrier in the treatment of breast cancer. Activation of the Akt-PI3K-mTOR pathway plays an important role in hormonal therapy resistance. Our recent preclinical and clinical studies showed that the addition of a histone deacetylase inhibitor re-sensitized hormonal therapy resistant breast cancer to tamoxifen. As histone deacetylases are key regulators of Akt, we evaluated the effect of combined treatment with the histone deacetylase inhibitor PCI-24781 and tamoxifen on Akt in breast cancer cells. We demonstrate that while both histone deacetylase and estrogen receptor inhibition down regulate AKT mRNA and protein, their concerted effort results in down regulation of AKT activity with induction of cell death. Histone deacetylase inhibition exerts its effect on AKT mRNA through an estrogen receptor-dependent mechanism, primarily down regulating the most abundant isoform AKT1. Although siRNA depletion of AKT modestly induces cell death, when combined with an anti-estrogen, cytotoxicity is significantly enhanced. Thus, histone deacetylase regulation of AKT mRNA is a key mediator of this therapeutic combination and may represent a novel biomarker for predicting response to this regimen. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
