BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
| Autor: | Sree C. Yaddanapudi, Teresa Ramon y Cajal, Adriana Dusso, Martin A. Neumann, David A Grotsky, Ignacio Gonzalez-Suarez, Junran Zhang, Abena B. Redwood, Xavier Matias-Guiu, Zhihui Feng, Sylvia Ortega-Martínez, Enrique Lerma, Monica Croke, Montserrat Martínez-Alonso, Susana Gonzalo, Anna Novell |
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| Rok vydání: | 2013 |
| Předmět: |
Genome instability
endocrine system diseases DNA Repair DNA repair Cathepsin L Breast Neoplasms Biology Calcitriol receptor Genomic Instability Article 03 medical and health sciences 0302 clinical medicine Breast cancer Cell Line Tumor medicine Humans skin and connective tissue diseases Germ-Line Mutation Research Articles Triple-negative breast cancer 030304 developmental biology Cathepsin 0303 health sciences BRCA1 Protein Intracellular Signaling Peptides and Proteins Cell Biology medicine.disease Molecular biology 3. Good health Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis biology.protein Biomarker (medicine) Female Tumor Suppressor p53-Binding Protein 1 |
| Zdroj: | The Journal of Cell Biology Recercat. Dipósit de la Recerca de Catalunya instname Repositorio Abierto de la UdL Universitad de Lleida |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Cathepsin L degrades 53BP1 to overcome genomic instability and growth arrest in BRCA1-deficient and triple-negative breast cancers. 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. |
| Databáze: | OpenAIRE |
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