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.
Highlights
5–10% of female breast cancer are believed to be hereditary, caused by a germline mutation in the BRCA1 or BRCA2 genes
We demonstrate that TOP1 and CDH3 are closely associated to BRCA1-deficient breast cancer
We report that TOP1 and CDH3 were expressed to a higher extent in BRCA1-related breast carcinomas relative to sporadic breast carcinomas, highlighting their potential clinical usefulness for breast cancer detection in women with a BRCA1 mutation
Summary
5–10% of female breast cancer are believed to be hereditary, caused by a germline mutation in the BRCA1 or BRCA2 genes. Owing to an increased lifetime cancer risk and young age of onset, mutation carriers are eligible for an intensified surveillance program consisting of clinical breast examination and www.impactjournals.com/oncotarget annual screening mammography with the intention to detect breast cancer at a potentially curable stage. The accuracy of screening mammography to detect early breast lesions is, limited in young women due to their dense breast tissue [1,2,3]. Magnetic resonance imaging as an adjunct to screening mammography has improved sensitivity to detect suspected breast lesions [4, 5], but interval breast cancer rates remain substantial and specificity is limited [6]. There is a compelling need to improve current clinical management i.e. early breast cancer detection in BRCA mutation carriers. The question remains whether this signature is applicable for routine clinical assessment, but our findings, together with other reports, underscore the usefulness of GEMMs and the potential of proteomics as an approach for discovery of novel protein biomarkers
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