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AKT-induced tamoxifen resistance is overturned by RRM2 inhibition.

AbstractUNLABELLED:
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.
AuthorsKhyati N Shah, Kshama R Mehta, David Peterson, Marie Evangelista, John C Livesey, Jesika S Faridi
JournalMolecular cancer research : MCR (Mol Cancer Res) Vol. 12 Issue 3 Pg. 394-407 (Mar 2014) ISSN: 1557-3125 [Electronic] United States
PMID24362250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • Isoenzymes
  • Tamoxifen
  • ribonucleotide reductase M2
  • Ribonucleoside Diphosphate Reductase
  • Proto-Oncogene Proteins c-akt
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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