Abstract | UNLABELLED: Acquired tamoxifen resistance develops in the majority of hormone-responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post- tamoxifen therapy under conditions of AKT overexpression. Consistent with the biologic outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNA interference (RNAi)-mediated approaches significantly reversed the tamoxifen-resistant cell growth, inhibited cell motility, and activated DNA damage and proapoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM inhibitor didox significantly reduced in vitro and in vivo growth. Thus, AKT-expressing breast cancer cells upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis. IMPLICATIONS: These findings identify RRM2 as an AKT-regulated gene, which plays a role in tamoxifen resistance and may prove to be a novel target for effective diagnostic and preventative strategies.
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Authors | Khyati N Shah, Kshama R Mehta, David Peterson, Marie Evangelista, John C Livesey, Jesika S Faridi |
Journal | Molecular cancer research : MCR
(Mol Cancer Res)
Vol. 12
Issue 3
Pg. 394-407
(Mar 2014)
ISSN: 1557-3125 [Electronic] United States |
PMID | 24362250
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents, Hormonal
- Estrogen Receptor alpha
- Isoenzymes
- Tamoxifen
- ribonucleotide reductase M2
- Ribonucleoside Diphosphate Reductase
- Proto-Oncogene Proteins c-akt
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Topics |
- Animals
- Antineoplastic Agents, Hormonal
(pharmacology)
- Breast Neoplasms
(drug therapy, genetics, metabolism, pathology)
- Cell Growth Processes
(drug effects)
- Cell Movement
(drug effects, physiology)
- Drug Resistance, Neoplasm
- Estrogen Receptor alpha
(biosynthesis)
- Female
- Humans
- Isoenzymes
- MCF-7 Cells
- Mice
- Neoplasms, Hormone-Dependent
(drug therapy, genetics, metabolism, pathology)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Ribonucleoside Diphosphate Reductase
(antagonists & inhibitors)
- Signal Transduction
- Tamoxifen
(pharmacology)
- Xenograft Model Antitumor Assays
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