title: Roscovitine confers tumor suppressive effect on therapy-resistant breast tumor cells.
abstract: BACKGROUND
  Current clinical strategies for treating hormonal breast cancer involve the use of anti-estrogens that block estrogen receptor (ER)α functions and aromatase inhibitors that decrease local and systemic estrogen production. Both of these strategies improve outcomes for ERα-positive breast cancer patients, however, development of therapy resistance remains a major clinical problem. Divergent molecular pathways have been described for this resistant phenotype and interestingly, the majority of downstream events in these resistance pathways converge upon the modulation of cell cycle regulatory proteins including aberrant activation of cyclin dependent kinase 2 (CDK2). In this study, we examined whether the CDK inhibitor roscovitine confers a tumor suppressive effect on therapy-resistant breast epithelial cells.
  
  
  METHODS
  Using various in vitro and in vivo assays, we tested the effect of roscovitine on three hormonal therapy-resistant model cells: (a) MCF-7-TamR (acquired tamoxifen resistance model); (b) MCF-7-LTLTca (acquired letrozole resistance model); and (c) MCF-7-HER2 that exhibit tamoxifen resistance (ER-growth factor signaling cross talk model).
  
  
  RESULTS
  Hormonal therapy-resistant cells exhibited aberrant activation of the CDK2 pathway. Roscovitine at a dose of 20 μM significantly inhibited the cell proliferation rate and foci formation potential of all three therapy-resistant cells. The drug treatment substantially increased the proportion of cells in G2/M cell cycle phase with decreased CDK2 activity and promoted low cyclin D1 levels. Interestingly, roscovitine also preferentially down regulated the ERα isoform and ER-coregulators including AIB1 and PELP1. Results from xenograft studies further showed that roscovitine can attenuate growth of therapy-resistant tumors in vivo.
  
  
  CONCLUSIONS
  Roscovitine can reduce cell proliferation and survival of hormone therapy-resistant breast cancer cells. Our results support the emerging concept that inhibition of CDK2 activity has the potential to abrogate growth of hormonal therapy-resistant cells.
authors.affiliation: Department of Obstetrics and Gynecology, CTRC at UT Health Science Center, San Antonio, Texas 78229, USA.
authors.forename: Binoj C
authors.initials: BC
authors.lastname: Nair
authors.forename: Sreeram
authors.initials: S
authors.lastname: Vallabhaneni
authors.forename: Rajeshwar R
authors.initials: RR
authors.lastname: Tekmal
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins / Q000096:biosynthesis / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D056970:Co-Repressor Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C438485:PELP1 protein, human; D047428:Protein Kinase Inhibitors; D011687:Purines; D014157:Transcription Factors; D000077546:Roscovitine; D019938:Cyclin D1; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2