Abstract
Abstract Background: Breast cancer is the most common malignancy in women in the western world. The outcome of breast cancer would be strongly improved if patients could be diagnosed and treated early. This especially holds for patients with hereditary breast cancer. Aim: The aim of this study is to identify novel protein biomarkers for early diagnosis of BRCA1 deficient breast cancer and for drug sensitivity. Approach: We used in-depth proteome profiling of tumor tissues of mouse breast cancer models to identify BRCA1-associated proteins. To this end, we analyzed tumor tissue lysates of three genetic mouse models: 1.the Brca1−/−;p53−/− mouse that develops breast tumors with histopathological and molecular features of BRCA1−/− basal-like breast cancers (N=6), 2. the ECAD−/−;p53−/− mouse with metastasizing mammary tumors resembling human invasive lobular cancer (N=3) and 3. the p53−/− mouse that develops diverse mammary tumors (N=3). Total tumor tissue lysates were fractionated using SDS-PAGE followed by tryptic in-gel digestion, nanoLC-MS/MS and database searching. Normalized spectral counting was used for protein quantification and beta binomial statistics to discover significantly regulated proteins. Ingenuity Pathway Analysis (IPA) was used to support data interpretation. Results: The total dataset contained 3836 identified proteins of which 804 were significantly regulated between the BRCA1 deficient and proficient groups (p<0.05), with over 500 proteins up-regulated in the BRCA1 deficient tumors, including proteins previously implicated in BRCA1 breast cancer. Pathway analysis revealed that many up-regulated proteins were involved in DNA-repair. Integration with breast cancer cell line secretome data indicated the non-invasive biomarker potential for a large subset of candidates. Integration with transcriptomics data obtained for a series of human genetic and sporadic breast cancer tissues indicated a large overlap of BRCA1 protein and RNA candidates. Moreover, the BRCA1-associated mouse proteins could almost perfectly classify human basal BRCA1 tumors. Currently, selected candidates are being followed up using immunohistochemical staining of a set of human BRCA1 deficient and sporadic tumors. Conclusion: We conclude that proteomics of genetic mouse models for genetic breast cancer is a powerful strategy to discover novel candidate BRCA1 DNA-repair-deficiency proteins with human relevance. Further validation studies are required to investigate whether these candidates are robust biomarkers for early detection of BRCA1 tumors and whether they are also indicative for sensitivity to PARP inhibition in non-BRCA1-deficient-tumors. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4563.
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