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dc.contributor.authorGrotsky, David A.
dc.contributor.authorGonzález-Suárez, Ignacio
dc.contributor.authorNovell Álvarez, Anna
dc.contributor.authorNeumann, Martin
dc.contributor.authorYaddanapudi, Sree C.
dc.contributor.authorCroke, Monica
dc.contributor.authorMartínez Alonso, Montserrat
dc.contributor.authorRedwood, Abena B.
dc.contributor.authorOrtega-Martinez, Sylvia
dc.contributor.authorFeng, Zhihui
dc.contributor.authorLerma, Enrique
dc.contributor.authorRamon y Cajal, Teresa
dc.contributor.authorZhang, Junran
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorDusso Rosso, Adriana
dc.contributor.authorGonzalo, Susana
dc.description.abstractLoss 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.ca_ES
dc.publisherThe Rockefeller University Pressca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofJournal of Cell Biology, 2005, vol. 200, núm. 2, p. 187-202ca_ES
dc.rightscc-by-nc-sa, (c) Grotsky et al., 2013ca_ES
dc.titleBRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cellsca_ES

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cc-by-nc-sa, (c) Grotsky et al., 2013
Except where otherwise noted, this item's license is described as cc-by-nc-sa, (c) Grotsky et al., 2013