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BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells

Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss...

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Autores principales: Grotsky, David A., Gonzalez-Suarez, Ignacio, Novell, Anna, Neumann, Martin A., Yaddanapudi, Sree C., Croke, Monica, Martinez-Alonso, Montserrat, Redwood, Abena B., Ortega-Martinez, Sylvia, Feng, Zhihui, Lerma, Enrique, Ramon y Cajal, Teresa, Zhang, Junran, Matias-Guiu, Xavier, Dusso, Adriana, Gonzalo, Susana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549967/
https://www.ncbi.nlm.nih.gov/pubmed/23337117
http://dx.doi.org/10.1083/jcb.201204053
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author Grotsky, David A.
Gonzalez-Suarez, Ignacio
Novell, Anna
Neumann, Martin A.
Yaddanapudi, Sree C.
Croke, Monica
Martinez-Alonso, Montserrat
Redwood, Abena B.
Ortega-Martinez, Sylvia
Feng, Zhihui
Lerma, Enrique
Ramon y Cajal, Teresa
Zhang, Junran
Matias-Guiu, Xavier
Dusso, Adriana
Gonzalo, Susana
author_facet Grotsky, David A.
Gonzalez-Suarez, Ignacio
Novell, Anna
Neumann, Martin A.
Yaddanapudi, Sree C.
Croke, Monica
Martinez-Alonso, Montserrat
Redwood, Abena B.
Ortega-Martinez, Sylvia
Feng, Zhihui
Lerma, Enrique
Ramon y Cajal, Teresa
Zhang, Junran
Matias-Guiu, Xavier
Dusso, Adriana
Gonzalo, Susana
author_sort Grotsky, David A.
collection PubMed
description Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)–mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate–ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy.
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spelling pubmed-35499672013-07-21 BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells Grotsky, David A. Gonzalez-Suarez, Ignacio Novell, Anna Neumann, Martin A. Yaddanapudi, Sree C. Croke, Monica Martinez-Alonso, Montserrat Redwood, Abena B. Ortega-Martinez, Sylvia Feng, Zhihui Lerma, Enrique Ramon y Cajal, Teresa Zhang, Junran Matias-Guiu, Xavier Dusso, Adriana Gonzalo, Susana J Cell Biol Research Articles Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)–mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate–ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy. The Rockefeller University Press 2013-01-21 /pmc/articles/PMC3549967/ /pubmed/23337117 http://dx.doi.org/10.1083/jcb.201204053 Text en © 2013 Grotsky et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Grotsky, David A.
Gonzalez-Suarez, Ignacio
Novell, Anna
Neumann, Martin A.
Yaddanapudi, Sree C.
Croke, Monica
Martinez-Alonso, Montserrat
Redwood, Abena B.
Ortega-Martinez, Sylvia
Feng, Zhihui
Lerma, Enrique
Ramon y Cajal, Teresa
Zhang, Junran
Matias-Guiu, Xavier
Dusso, Adriana
Gonzalo, Susana
BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
title BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
title_full BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
title_fullStr BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
title_full_unstemmed BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
title_short BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
title_sort brca1 loss activates cathepsin l–mediated degradation of 53bp1 in breast cancer cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549967/
https://www.ncbi.nlm.nih.gov/pubmed/23337117
http://dx.doi.org/10.1083/jcb.201204053
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