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Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative

Breast cancer is the second leading cause of cancer-related deaths in women. Triple negative breast cancer (TNBC) is an aggressive subtype that affects 10–25% mostly African American women. TNBC has the poorest prognosis of all subtypes with rapid progression leading to mortality in younger patients...

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Autores principales: Blanchard, Zannel, Mullins, Nicole, Ellipeddi, Pavani, Lage, Janice M., McKinney, Shawn, El-Etriby, Rana, Zhang, Xu, Isokpehi, Raphael, Hernandez, Brenda, ElShamy, Wael M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005756/
https://www.ncbi.nlm.nih.gov/pubmed/24789045
http://dx.doi.org/10.1371/journal.pone.0095663
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author Blanchard, Zannel
Mullins, Nicole
Ellipeddi, Pavani
Lage, Janice M.
McKinney, Shawn
El-Etriby, Rana
Zhang, Xu
Isokpehi, Raphael
Hernandez, Brenda
ElShamy, Wael M.
author_facet Blanchard, Zannel
Mullins, Nicole
Ellipeddi, Pavani
Lage, Janice M.
McKinney, Shawn
El-Etriby, Rana
Zhang, Xu
Isokpehi, Raphael
Hernandez, Brenda
ElShamy, Wael M.
author_sort Blanchard, Zannel
collection PubMed
description Breast cancer is the second leading cause of cancer-related deaths in women. Triple negative breast cancer (TNBC) is an aggressive subtype that affects 10–25% mostly African American women. TNBC has the poorest prognosis of all subtypes with rapid progression leading to mortality in younger patients. So far, there is no targeted treatment for TNBC. To that end, here we show that c-Abl is one of several tyrosine kinases that phosphorylate and activate geminin’s ability to promote TNBC. Analysis of >800 breast tumor samples showed that geminin is overexpressed in ∼50% of all tumors. Although c-Abl is overexpressed in ∼90% of all tumors, it is only nuclear in geminin overexpressing tumors. In geminin-negative tumors, c-Abl is only cytoplasmic. Inhibiting c-Abl expression or activity (using imatinib or nilotinib) prevented geminin Y150 phosphorylation, inactivated the protein, and most importantly converted overexpressed geminin from an oncogene to an apoptosis inducer. In pre-clinical orthotopic breast tumor models, geminin-overexpressing cells developed aneuploid and invasive tumors, which were suppressed when c-Abl expression was blocked. Moreover, established geminin overexpressing orthotopic tumors regressed when treated with imatinib or nilotinib. Our studies support imatinib/nilotonib as a novel treatment option for patients with aggressive breast cancer (including a subset of TNBCs)-overexpressing geminin and nuclear c-Abl.
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spelling pubmed-40057562014-05-09 Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative Blanchard, Zannel Mullins, Nicole Ellipeddi, Pavani Lage, Janice M. McKinney, Shawn El-Etriby, Rana Zhang, Xu Isokpehi, Raphael Hernandez, Brenda ElShamy, Wael M. PLoS One Research Article Breast cancer is the second leading cause of cancer-related deaths in women. Triple negative breast cancer (TNBC) is an aggressive subtype that affects 10–25% mostly African American women. TNBC has the poorest prognosis of all subtypes with rapid progression leading to mortality in younger patients. So far, there is no targeted treatment for TNBC. To that end, here we show that c-Abl is one of several tyrosine kinases that phosphorylate and activate geminin’s ability to promote TNBC. Analysis of >800 breast tumor samples showed that geminin is overexpressed in ∼50% of all tumors. Although c-Abl is overexpressed in ∼90% of all tumors, it is only nuclear in geminin overexpressing tumors. In geminin-negative tumors, c-Abl is only cytoplasmic. Inhibiting c-Abl expression or activity (using imatinib or nilotinib) prevented geminin Y150 phosphorylation, inactivated the protein, and most importantly converted overexpressed geminin from an oncogene to an apoptosis inducer. In pre-clinical orthotopic breast tumor models, geminin-overexpressing cells developed aneuploid and invasive tumors, which were suppressed when c-Abl expression was blocked. Moreover, established geminin overexpressing orthotopic tumors regressed when treated with imatinib or nilotinib. Our studies support imatinib/nilotonib as a novel treatment option for patients with aggressive breast cancer (including a subset of TNBCs)-overexpressing geminin and nuclear c-Abl. Public Library of Science 2014-04-30 /pmc/articles/PMC4005756/ /pubmed/24789045 http://dx.doi.org/10.1371/journal.pone.0095663 Text en © 2014 Blanchard 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
Blanchard, Zannel
Mullins, Nicole
Ellipeddi, Pavani
Lage, Janice M.
McKinney, Shawn
El-Etriby, Rana
Zhang, Xu
Isokpehi, Raphael
Hernandez, Brenda
ElShamy, Wael M.
Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative
title Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative
title_full Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative
title_fullStr Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative
title_full_unstemmed Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative
title_short Geminin Overexpression Promotes Imatinib Sensitive Breast Cancer: A Novel Treatment Approach for Aggressive Breast Cancers, Including a Subset of Triple Negative
title_sort geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005756/
https://www.ncbi.nlm.nih.gov/pubmed/24789045
http://dx.doi.org/10.1371/journal.pone.0095663
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