title: BRCA1 loss activates cathepsin L-mediated degradation of 53BP1 in breast cancer cells.
abstract: 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.
authors: Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
authors: David A
authors: DA
authors: Grotsky
authors: Ignacio
authors: I
authors: Gonzalez-Suarez
authors: Anna
authors: A
authors: Novell
authors: Martin A
authors: MA
authors: Neumann
authors: Sree C
authors: SC
authors: Yaddanapudi
authors: Monica
authors: M
authors: Croke
authors: Montserrat
authors: M
authors: Martinez-Alonso
authors: Abena B
authors: AB
authors: Redwood
authors: Sylvia
authors: S
authors: Ortega-Martinez
authors: Zhihui
authors: Z
authors: Feng
authors: Enrique
authors: E
authors: Lerma
authors: Teresa
authors: T
authors: Ramon y Cajal
authors: Junran
authors: J
authors: Zhang
authors: Xavier
authors: X
authors: Matias-Guiu
authors: Adriana
authors: A
authors: Dusso
authors: Susana
authors: S
authors: Gonzalo
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D056668:Cathepsin L / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C534281:CTSL protein, human; D056668:Cathepsin L