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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 sh...

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Autores principales: Shimizu, Yoshiko, Luk, Hugh, Horio, David, Miron, Penelope, Griswold, Michael, Iglehart, Dirk, Hernandez, Brenda, Killeen, Jeffrey, ElShamy, Wael M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325250/
https://www.ncbi.nlm.nih.gov/pubmed/22511931
http://dx.doi.org/10.1371/journal.pone.0034102
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author Shimizu, Yoshiko
Luk, Hugh
Horio, David
Miron, Penelope
Griswold, Michael
Iglehart, Dirk
Hernandez, Brenda
Killeen, Jeffrey
ElShamy, Wael M.
author_facet Shimizu, Yoshiko
Luk, Hugh
Horio, David
Miron, Penelope
Griswold, Michael
Iglehart, Dirk
Hernandez, Brenda
Killeen, Jeffrey
ElShamy, Wael M.
author_sort Shimizu, Yoshiko
collection PubMed
description 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.
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spelling pubmed-33252502012-04-17 BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers Shimizu, Yoshiko Luk, Hugh Horio, David Miron, Penelope Griswold, Michael Iglehart, Dirk Hernandez, Brenda Killeen, Jeffrey ElShamy, Wael M. PLoS One Research Article 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. Public Library of Science 2012-04-12 /pmc/articles/PMC3325250/ /pubmed/22511931 http://dx.doi.org/10.1371/journal.pone.0034102 Text en Shimizu et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Shimizu, Yoshiko
Luk, Hugh
Horio, David
Miron, Penelope
Griswold, Michael
Iglehart, Dirk
Hernandez, Brenda
Killeen, Jeffrey
ElShamy, Wael M.
BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers
title BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers
title_full BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers
title_fullStr BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers
title_full_unstemmed BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers
title_short BRCA1-IRIS Overexpression Promotes Formation of Aggressive Breast Cancers
title_sort brca1-iris overexpression promotes formation of aggressive breast cancers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325250/
https://www.ncbi.nlm.nih.gov/pubmed/22511931
http://dx.doi.org/10.1371/journal.pone.0034102
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