Introduction: 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

ElShamy, Wael M.

Griswold, Michael

Hernandez, Brenda

Horio, David

Iglehart, Dirk

Killeen, Jeffrey

Luk, Hugh

Miron, Penelope

Shimizu, Yoshiko

English

PubMed

<div><h3>Introduction</h3><p>Women with HER2<sup>+</sup> 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, <em>BRCA1</em> 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<sup>+</sup> and/or TN/BL tumors.</p> <h3>Methodology/Principal Findings</h3><p>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<sup>V12</sup>-overexpressing HME cells. Induction of primary and invasive rat mammary tumors using the carcinogen <em>N</em>-methyl-<em>N</em>-nitrosourea (NMU), followed by analysis of rat <em>BRCA1-IRIS</em> and <em>ERα</em> mRNA levels in these tumors.</p> <p>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<sup>+</sup> 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 <em>BRCA1-IRIS</em> mRNA but low levels of rat <em>ERα</em> mRNA.</p> <h3>Conclusion/Significance</h3><p>BRCA1-IRIS overexpression triggers aggressive breast tumor formation, especially in patients with HER2<sup>+</sup> 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.</p> </div

Yoshiko Shimizu (171960)

Hugh Luk (171965)

David Horio (171970)

Penelope Miron (171974)

Michael Griswold (171977)

Dirk Iglehart (171981)

Brenda Hernandez (171985)

Jeffrey Killeen (171990)

Wael M. ElShamy (171996)

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BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers

INTRODUCTION: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSION/SIGNIFICANCE: 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

Yoshiko Shimizu

Hugh Luk

David Horio

Penelope Miron

Michael Griswold

Dirk Iglehart

Brenda Hernandez

Jeffrey Killeen

Wael M ElShamy

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PLoS ONE

BRCA1-IRIS overexpression promotes formation of aggressive breast cancers.

 and/or TN/BL tumors. mRNA. 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

Shimizu Yoshiko

Luk Hugh

Horio David

Miron Penelope

Griswold Michael

Iglehart Dirk

Hernandez Brenda

Killeen Jeffrey

ElShamy Wael M.

Public Library of Science (PLOS)

Abstract
               Introduction: Women with Her2+ or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly and early in life, due in part to Herceptin resistance that develops in Her2+ patients and because of the lack of appropriate therapies for TN/BL patients. Great effort is being made now to uncover appropriate drug targets to overcome these shortcomings. In this report we examine whether BRCA1-IRIS can be a valuable treatment target for Her2+ and/or TN/BL tumors. Methods: Immunohistochemistry (IHC) staining of breast tumor samples using a newly generated mouse monoclonal anti-BRCA1-IRIS antibody was performed. BRCA1-IRIS expression was correlated to that of AKT1, AKT2, p-AKT, survivin, ER[[Unsupported Character - Symbol Font &amp;#61537;]], PR, and BRCA1/p220 expression detected using commercial antibodies. Where available, patients’ tumor grade, tumor stage, age at diagnosis, and node positivity were also compared. We also generated subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing BRCA1-IRIS and then compared AKT and survivin expression, and tumor phenotype and aggressiveness to RasV12-induced tumors. Results: The majority of human breast tumors, especially Her2+ and TN/BL tumors, were BRCA1-IRIS-positive. These tumors also expressed high levels of AKT1, AKT2, p-AKT, and survivin, but were ER[[Unsupported Character - Symbol Font &amp;#61537;]]-, PR-, and BRCA1/p220-negative. BRCA1-IRIS overexpressing Her2+ and TN/BL tumors were high-grade tumors, and showed lymph-node positivity and/or distant metastasis compared to those not overexpressing BRCA1-IRIS. BRCA1-IRIS overexpression also significantly reduced the age at which patients with Her2+ or TN/BL tumors were diagnosed compared to patients with the same tumors but negative for BRCA1/IRIS (51.4±16.2 vs. 64.5±13.2, p≤0.05 for Her2+ and 48.9±10.1 vs. 70.8±6.8, p≤0.01 for TN/BL). Surprisingly, TN/BL/BRCA1-IRIS-positive tumors were larger than Her2+/BRCA1-IRIS-positive tumors (30.6±19.3 vs. 16.1±9.7, p≤0.05). HME cells overexpressing BRCA1-IRIS developed tumors when injected subcutaneously in SCID mice. These tumors were invasive and showed high expression levels of AKT1, AKT2, and p-AKT when compared to RasV12-induced tumors. These tumors also overexpressed the mesenchymal protein vimentin, but did not express the epithelial proteins CK19 and p63, and were BRCA1/p220-negative. In contrast, the less aggressive RasV12-induced tumors expressed CK19, p63, and BRCA1/p220, but not vimentin. Conclusion: These data demonstrate that BRCA1-IRIS overexpression triggers aggressive breast tumor formation, especially in patients with tumors of the Her2+ or TN/BL subtypes. We propose that BRCA1-IRIS inhibition may be used as a novel therapeutic option for the treatment of aggressive breast tumors of the Her2+ and/or TN/BL subtype.
               Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5319. doi:1538-7445.AM2012-5319</jats:p

Wael M. ElShamy

Crossref

Cancer Research

Abstract 5319: BRCA1-IRIS overexpression promotes formation of aggressive breast cancers

http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.270.1762

BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers

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