Résumé
Purpose: BRCA1 plays a key role in DNA repair and cellular stress response. Inhibitors of PARP show promising clinical activity in metastatic, triple-negative BRCA-mutated breast cancer. P53 binding protein 1 (53BP1) is a protein involved in DNA damage checkpoint activation and DNA repair that is involved in both non homologous end-joining and homology-mediated repair of double-strand DNA breaks. When both BRCA1 and 53BP1 are lost, homology-mediated repair appears to be restored and the sensitivity to DNA damaging agents is reduced. Loss of 53BP1 leads to resistance to cis-platinum and PARP inhibitors in BRCA1-deficient cells, suggesting that 53BP1 is a critical modulator of repair choice in BRCA1 mutant, and possibly epigenetically inactivated cells. Reduced 53BP1 expression has been reported in sporadic basal-like and triple-negative and BRCA-associated breast cancers. It thus appears important to simultaneously evaluate 53BP1 status altogether with BRCA1 mutation/methylation in order to estimate the homology-mediated functionality in breast cancer tumors.
Methods: We investigated cytosolic 53BP1 levels and BRCA1 gene promoter hypermethylation profile in 151 surgical tumor samples from patients treated in our institution between January 2006 and November 2009 and evaluated their statistical association with classical breast cancer predictive and prognostic factors. DNA methylation patterns in the CpG islands of BRCA1 gene promoter were determined by a methylation specific PCR distinguishing unmethylated from methylated alleles in a given gene on the basis of sequence changes produced following bisulfite treatment of DNA. Cytosolic 53BP1 level was evaluated using a commercially available assay kit.
Results: Median age was 54 years (range 29-75 years). Median 53BP1 protein level (pg/mg of cytosolic protein) was 9.5. Using this cut-off, low 53BP1 levels were significantly associated with negative ER and PR status, triple-negative profile, low cytosolic PARP activity, BRCA1 promoter hypermethylation and absence of nodal metastases. The hypermethylation status was significantly associated with UPA and PAI-1 levels, SBR grade, SBR Mitotic count score, ER, PR and HER-2 negative status, and then conversely triple negative (ER, PR and HER-2 negative) profile. Twenty nine percent of the triple negative tumors presented a hypermethylated status, comparing to 5 and 2% for HR+/HER-2- and HER-2+ tumors respectively. In the triple negative population (N=48), only 2 of the 13 tumors with BRCA1 promoter hypermethylation, presented high (>9.5 pg/mg) 53BP1 protein levels
Conclusion: Triple negative breast cancers harboring simultaneously a high level of 53BP1 and BRCA1 promoter hypermethylation are a putative target population for development of drugs targeting DNA repair. However, this population appears to be restricted to a small subgroup of triple negative breast cancers.
Citation Format: William Jacot, Simon Thezenas, Anne-Claire Laberenne, Romain Senal, Cathy Viglianti, Frédéric Bibeau, Jean-Pierre Bleuse, Gilles Romieu, Pierre-Jean Lamy. Frequent BRCA1 promoter methylation and low 53BP1 status in sporadic triple-negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1770. doi:10.1158/1538-7445.AM2013-1770