title: Secretome proteomics reveals candidate non-invasive biomarkers of BRCA1 deficiency in breast cancer.
abstract: Breast cancer arising in female BRCA1 mutation carriers is characterized by an aggressive phenotype and early age of onset. We performed tandem mass spectrometry-based proteomics of secretomes and exosome-like extracellular vesicles from BRCA1-deficient and BRCA1-proficient murine breast tumor models to identify extracellular protein biomarkers, which can be used as an adjunct to current diagnostic modalities in patients with BRCA1-deficient breast cancer. We identified 2,107 proteins, of which 215 were highly enriched in the BRCA1-deficient secretome. We demonstrated that BRCA1-deficient secretome proteins could cluster most human BRCA1- and BRCA2-related breast carcinomas at the transcriptome level. Topoisomerase I (TOP1) and P-cadherin (CDH3) expression was investigated by immunohistochemistry on tissue microarrays of a large panel of 253 human breast carcinomas with and without BRCA1/2 mutations. We showed that expression of TOP1 and CDH3 was significantly increased in human BRCA1-related breast carcinomas relative to sporadic cases (p = 0.002 and p < 0.001, respectively). Multiple logistic regression showed that TOP1 (adjusted odds ratio [OR] 3.75; 95% confidence interval [95% CI], 1.85 - 7.71, p < 0.001) as well as CDH3 positivity (adjusted OR 2.45; 95% CI, 1.08 - 5.49, p = 0.032) were associated with BRCA1/2-related breast carcinomas after adjustment for triple-negative phenotype and age. In conclusion, proteome profiling of secretome using murine breast tumor models is a powerful strategy to identify non-invasive candidate biomarkers of BRCA1-deficient breast cancer. We demonstrate that TOP1 and CDH3 are closely associated to BRCA1-deficient breast cancer. These data merit further investigation for early detection of tumors arising in BRCA1 mutation carriers.
authors: Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Marc
authors: M
authors: Warmoes
authors: Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Siu W
authors: SW
authors: Lam
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Petra
authors: P
authors: van der Groep
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Janneke E
authors: JE
authors: Jaspers
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Yvonne H C M
authors: YH
authors: Smolders
authors: Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Leon
authors: L
authors: de Boer
authors: Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Thang V
authors: TV
authors: Pham
authors: Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Sander R
authors: SR
authors: Piersma
authors: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Switzerland.
authors: Sven
authors: S
authors: Rottenberg
authors: Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Epie
authors: E
authors: Boven
authors: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors: Jos
authors: J
authors: Jonkers
authors: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Paul J
authors: PJ
authors: van Diest
authors: Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Connie R
authors: CR
authors: Jimenez
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D020543:Proteome / Q000032:analysis*; D040901:Proteomics / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D020543:Proteome
keywords: BRCA1; biomarkers; breast cancer; proteomics