title: Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors.
abstract: BACKGROUND
  The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown.
  
  
  METHODS
  We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types.
  
  
  RESULTS
  Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-ΔEx3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-ΔEx3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis.
  
  
  CONCLUSIONS
  Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.
authors.forename: Alice
authors.initials: A
authors.lastname: Faversani
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.forename: Giacomina P
authors.initials: GP
authors.lastname: Moro
authors.forename: Delfina
authors.initials: D
authors.lastname: Tosi
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.forename: David C
authors.initials: DC
authors.lastname: Schultz
authors.forename: Dayana
authors.initials: D
authors.lastname: Rivadeneira
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
mesh_terms: D017398:Alternative Splicing; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D061986:MCF-7 Cells; D009285:Naphthoquinones / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D004317:Doxorubicin; D005047:Etoposide; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C107489:BIRC5 protein, human; C508053:ERBB2 protein, human; C523798:sepantronium