title: BRCA1-IRIS overexpression promotes formation of aggressive breast cancers.
abstract: BACKGROUND
  Women with HER2(+) or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly due, in part to acquired Herceptin resistance and lack of TN/BL-targeted therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2(+) and/or TN/BL tumors.
  
  
  RESULTS
  Immunohistochemical staining of large cohort of human breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT, survivin and BRCA1/p220, tumor status and age at diagnosis. Generation of subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT, survivin, and BRCA1/p220 expression, tumor status and aggressiveness in these tumors to that in tumors developed using TERT/LT/Ras(V12)-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen N-methyl-N-nitrosourea (NMU), followed by analysis of rat BRCA1-IRIS and ERα mRNA levels in these tumors. High BRCA1-IRIS expression was detected in the majority of human breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-, survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2(+) or TN/BL tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous tumors that express high AKT1, AKT2, p-AKT and vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast cancers expressed high levels of rat BRCA1-IRIS mRNA but low levels of rat ERα mRNA.
  
  
  CONCLUSIONS
  BRCA1-IRIS overexpression triggers aggressive breast tumor formation, especially in patients with HER2(+) or TN/BL subtypes. We propose that BRCA1-IRIS inhibition may be pursued as a novel therapeutic option to treat these aggressive breast tumor subtypes.
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Hugh
authors.initials: H
authors.lastname: Luk
authors.forename: David
authors.initials: D
authors.lastname: Horio
authors.forename: Penelope
authors.initials: P
authors.lastname: Miron
authors.forename: Michael
authors.initials: M
authors.lastname: Griswold
authors.forename: Dirk
authors.initials: D
authors.lastname: Iglehart
authors.forename: Brenda
authors.initials: B
authors.lastname: Hernandez
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Killeen
authors.forename: Wael M
authors.initials: WM
authors.lastname: ElShamy
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D051381:Rats; D015854:Up-Regulation
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human