title: Dicer-mediated upregulation of BCRP confers tamoxifen resistance in human breast cancer cells.
abstract: OBJECTIVE
  Tamoxifen (Tam) is the most prescribed hormonal agent for treatment of estrogen receptor α (ERα)-positive breast cancer patients. Using microarray analysis, we observed that metastatic breast tumors resistant to Tam therapy had elevated levels of Dicer.
  
  
  METHODS
  We overexpressed Dicer in ERα-positive MCF-7 human breast cancer cells and observed a concomitant increase in expression of the breast cancer resistance protein (BCRP). We thus hypothesized that Tam resistance associated with Dicer overexpression in ERα-positive breast cancer cells may involve BCRP. We analyzed BCRP function in Dicer-overexpressing cells using growth in soft agar and mammosphere formation and evaluated intracellular Tam efflux.
  
  
  RESULTS
  In the presence of Tam, Dicer-overexpressing cells formed resistant colonies in soft agar, and treatment with BCRP inhibitors restored Tam sensitivity. Tumor xenograft studies confirmed that Dicer-overexpressing cells were resistant to Tam in vivo. Tumors and distant metastases could be initiated with as few as five mammosphere cells from both vector and Dicer-overexpressing cells, indicating that the mammosphere assay selected for cells with enhanced tumor-initiating and metastatic capacity. Dicer-overexpressing cells with elevated levels of BCRP effluxed Tam more efficiently than control cells, and BCRP inhibitors were able to inhibit efflux.
  
  
  CONCLUSIONS
  Dicer-overexpressing breast cancer cells enriched for cells with enhanced BCRP function. We hypothesize that it is this population which may be involved in the emergence of Tam-resistant growth. BCRP may be a novel clinical target to restore Tam sensitivity.
authors: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA.
authors: Jennifer
authors: J
authors: Selever
authors: Guowei
authors: G
authors: Gu
authors: Michael T
authors: MT
authors: Lewis
authors: Amanda
authors: A
authors: Beyer
authors: Matthew H
authors: MH
authors: Herynk
authors: Kyle R
authors: KR
authors: Covington
authors: Anna
authors: A
authors: Tsimelzon
authors: Gabriela
authors: G
authors: Dontu
authors: Patrick
authors: P
authors: Provost
authors: Attilio
authors: A
authors: Di Pietro
authors: Ahcène
authors: A
authors: Boumendjel
authors: Kathy
authors: K
authors: Albain
authors: Lucio
authors: L
authors: Miele
authors: Heidi
authors: H
authors: Weiss
authors: Ines
authors: I
authors: Barone
authors: Sebastiano
authors: S
authors: Ando
authors: Suzanne A W
authors: SA
authors: Fuqua
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics; D043244:Ribonuclease III / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D013629:Tamoxifen; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases