title: Modeling luminal breast cancer heterogeneity: combination therapy to suppress a hormone receptor-negative, cytokeratin 5-positive subpopulation in luminal disease.
abstract: BACKGROUND
  Many Luminal breast cancers are heterogeneous, containing substantial numbers of estrogen (ER) and progesterone (PR) receptor-negative cells among the ER+ PR+ ones. One such subpopulation we call "Luminobasal" is ER-, PR- and cytokeratin 5 (CK5)-positive. It is not targeted for treatment.
  
  
  METHODS
  To address the relationships between ER+PR+CK5- and ER-PR-CK5+ cells in Luminal cancers and tightly control their ratios we generated isogenic pure Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal human breast cancer cell line. We used high-throughput screening to identify pLB-specific drugs and examined their efficacy alone and in combination with hormone therapy in mixed-cell tumor models.
  
  
  RESULTS
  We show that pLUM and MCF7 cells suppress proliferation of pLB cells in mixed-cell 3D colonies in vitro and that pLUM cells suppress growth of pLB cells in mixed-cell xenografts in vivo. High-throughput screening of 89 FDA-approved oncology drugs shows that pLB cells are sensitive to monotherapy with the epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib. By exploiting mixed-cell 3D colonies and mixed-cell solid mouse tumors models we demonstrate that combination therapy with gefitinib plus the anti-estrogen fulvestrant constitutes a robust treatment strategy.
  
  
  CONCLUSIONS
  We propose that response to combination endocrine/EGFR inhibitor therapies in heterogeneous Luminal cancers may improve long-term survival in patients whose primary tumors have been preselected for appropriate biomarkers, including ER, PR, CK5 and EGFR.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Knox
authors.forename: Allison L
authors.initials: AL
authors.lastname: Scaling
authors.forename: Mauricio P
authors.initials: MP
authors.lastname: Pinto
authors.forename: Brian S
authors.initials: BS
authors.lastname: Bliesner
authors.forename: James M
authors.initials: JM
authors.lastname: Haughian
authors.forename: Hany A
authors.initials: HA
authors.lastname: Abdel-Hafiz
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Horwitz
mesh_terms: D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008954:Models, Biological; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries
chemical_list: D015415:Biomarkers; D053555:Keratin-5; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D054852:Small Molecule Libraries; D066246:ErbB Receptors