title: AKT-induced tamoxifen resistance is overturned by RRM2 inhibition.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, 751 Brookside Road, Stockton, CA 95211. jfaridi@pacific.edu.
authors.forename: Khyati N
authors.initials: KN
authors.lastname: Shah
authors.forename: Kshama R
authors.initials: KR
authors.lastname: Mehta
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.forename: John C
authors.initials: JC
authors.lastname: Livesey
authors.forename: Jesika S
authors.initials: JS
authors.lastname: Faridi
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007527:Isoenzymes; D061986:MCF-7 Cells; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D007527:Isoenzymes; D013629:Tamoxifen; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D051057:Proto-Oncogene Proteins c-akt