title: BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers.
abstract: BACKGROUND
  Intrinsic or acquired chemoresistance is a major problem in oncology. Although highly responsive to chemotherapies such as paclitaxel, most triple negative breast cancer (TNBC) patients develop chemoresistance. Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences.
  
  
  METHODS
  We analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. We also analyzed a large cohort of breast tumor samples for BRCA1-IRIS, Forkhead box class O3a (FOXO3a) and survivin expression. Finally, we analyzed the effect of BRCA1-IRIS silencing or inactivation on TNBCs formation, maintenance and response to paclitaxel in an orthotopic model.
  
  
  RESULTS
  We show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. This signaling pathway is intact in TNBCs endogenously overexpressing BRCA1-IRIS. These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. Finally, we show BRCA1-IRIS and survivin overexpression is correlated with lack of FOXO3a expression in a large cohort of primary tumor samples, and that BRCA1-IRIS overexpression-induced signature is associated with decreased disease free survival in heavily treated estrogen receptor alpha-negative patients.
  
  
  CONCLUSIONS
  In addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. These loops activate AKT, causing FOXO3a degradation and survivin overexpression. Taken together, this underscores the need for BRCA1-IRIS-specific therapy and strongly suggests that BRCA1-IRIS and/or signaling loops activated by it could be rational therapeutic targets for advanced TNBCs.
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA. zblanchard@umc.edu.
authors.forename: Zannel
authors.initials: Z
authors.lastname: Blanchard
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA. bpaul@uchc.edu.|Present address: University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. bpaul@uchc.edu.
authors.forename: Bibbin T
authors.initials: BT
authors.lastname: Paul
authors.affiliation: Department of Medicine, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA. bcraft@umc.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Craft
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA. welshamy@umc.edu.
authors.forename: Wael M
authors.initials: WM
authors.lastname: ElShamy
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D059748:Proteolysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D000077022:Survivin; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D000077022:Survivin; D066246:ErbB Receptors; D017239:Paclitaxel