Secretome proteomics reveals candidate non-invasive biomarkers of BRCA1 deficiency in breast cancer
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Marc Warmoes1,*, Siu W. Lam1,*, Petra van der Groep2,3, Janneke E. Jaspers4,5, Yvonne H.C.M. Smolders2, Leon de Boer1, Thang V. Pham1, Sander R. Piersma1, Sven Rottenberg5,6, Epie Boven1, Jos Jonkers4, Paul J. van Diest2, Connie R. Jimenez1
1Oncoproteomics Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
2Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
3Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
4Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
5Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
6Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
*These authors contributed equally to this work
Connie R. Jimenez, email: [email protected]
Keywords: proteomics, biomarkers, BRCA1, breast cancer
Received: May 11, 2016 Accepted: August 13, 2016 Published: August 23, 2016
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.
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