Abstract
Most deaths from breast cancer result from tumor recurrence, but mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is downregulated during tumor recurrence and that Par-4 downregulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in patients with breast cancer, and Par-4 is downregulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / physiology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / etiology*
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Cardiac Myosins / metabolism
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Death-Associated Protein Kinases
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Down-Regulation
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Female
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Humans
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Mice
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Myosin Light Chains / metabolism
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Neoplasm Recurrence, Local / etiology*
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Phosphorylation
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Receptor, ErbB-2 / analysis
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Tumor Suppressor Protein p53 / physiology
Substances
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Apoptosis Regulatory Proteins
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Myosin Light Chains
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Tumor Suppressor Protein p53
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myosin light chain 2
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prostate apoptosis response-4 protein
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ERBB2 protein, human
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Receptor, ErbB-2
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Death-Associated Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Cardiac Myosins