Note: In May 2013 Angela Jolie had a double mastectomy after learning that she had BRCA1 gene which results in breast cancer in more than half of all females
From a presentation at Vitamin D Workshop in June 2013
See also VitaminDWiki
- Overview Breast Cancer and Vitamin D
- Search VitaminDWiki for BRCA1 7 items as of Oct 2013
- The “Deadly Breast Cancer Gene” Is A Myth, Lancet Study Confirms – Jan 2018
BRCA1 loss activates cathepsin L–mediated degradation of 53BP1 in breast cancer cells
Journal of Cell Biology; vol. 200 no. 2 187-202
David A. Grotsky 1,2,3; Ignacio Gonzalez-Suarez 2,3; Anna Novell 4,
Martin A. Neumann 1,2,3; Sree C. Yaddanapudi 2,3; Monica Croke 1,
Montserrat Martinez-Alonso 4; Abena B. Redwood 2,3; Sylvia Ortega-Martinez2,3,
Zhihui Feng 2,5; Enrique Lerma 6,7; Teresa Ramon y Cajal6,7,
Junran Zhang 2,5; Xavier Matias-Guiu 4; Adriana Dusso2,4, and
Susana Gonzalo1,2,3 sgonzalo@slu.edu
1Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104
2Department of Radiation Oncology and 3Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63108
4Department of Pathology, Molecular Genetics, and Nephrology, Hospital Universitario Arnau de Vilanova, Universidad de Lleida, Institute of Biomedical Research in Lleida, Lleida 25198, Spain
5Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH 44106
6Department of Pathology and 7Department of Medical Oncology, Hospital Santa Creu I Sant Pau, Barcelona 08025, Spain
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.
Submitted: 10 April 2012; Accepted: 13 December 2012
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