BRCA1 promoter hypermethylation, 53BP1 protein expression and PARP-1 activity as biomarkers of DNA repair deficit in breast cancer

BMC Cancer

William Jacot¹  Simon Thezenas³  Romain Senal²  Cathy Viglianti²  Anne-Claire Laberenne²  Evelyne Lopez-Crapez²  Frédéric Bibeau⁵  Jean-Pierre Bleuse³  Gilles Romieu⁴  Pierre-Jean Lamy² 

[1] Translational Research Unit, Montpellier Cancer Institute, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France

[2] Department of Biology and Oncogenetic, Montpellier Cancer Institute, Montpellier, France

[3] Department of Biostatistics, Montpellier Cancer Institute, Montpellier, France

[4] Department of Medical Oncology, Montpellier Cancer Institute, Montpellier, France

[5] Department of Pathology, Montpellier Cancer Institute, Montpellier, France

关键词: Methylation;    BRCA;    53BP1;    PARP-1;    Breast cancer;   

Others  :  1079470
DOI  :  10.1186/1471-2407-13-523

 received in 2013-06-28, accepted in 2013-10-23,  发布年份 2013

【 摘 要 】

Background

Poly(adenosine diphosphate–ribose) polymerase 1 (PARP-1) and the balance between BRCA1 and 53BP1 play a key role in the DNA repair and cell stress response. PARP inhibitors show promising clinical activity in metastatic triple negative (TN) or BRCA-mutated breast cancer. However, a comprehensive analysis of PARP-1 activity, BRCA1 promoter methylation and 53BP1 expression in tumours without known BRCA1 mutation has not yet been carried out.

Methods

We investigated cytosolic PARP-1 activity, 53BP1 protein levels and BRCA1 promoter methylation in 155 surgical breast tumour samples from patients without familial breast cancer history or known BRCA1 mutations who were treated between January 2006 and November 2009 and evaluated their statistical association with classical predictive and prognostic factors.

Results

The mitotic count score was the only parameter clearly associated with PARP-1 activity. BRCA1 promoter hypermethylation (15.4% of all cancers) was significantly associated with uPA and PAI-1 levels, tumour grade, mitotic count score, hormone receptor and HER2 negative status and TN profile (29% of TN tumours showed BRCA1 promoter hypermethylation compared to 5% of grade II-III hormone receptor-positive/HER2-negative and 2% of HER2-positive tumours). No statistical association was found between BRCA1 promoter hypermethylation and PARP-1 activity. High 53BP1 protein levels correlated with lymph node positivity, hormone receptor positivity, molecular grouping, unmethylated BRCA1 promoter and PARP-1 activity. In TN tumours, BRCA1 promoter methylation was only marginally associated with age, PARP-1 activity was not associated with any of the tested clinico-pathological factors and high 53BP1 protein levels were significantly associated with lymph node positivity. Only 3 of the 14 TN tumours with BRCA1 promoter hypermethylation presented high 53BP1 protein levels.

Conclusions

Breast cancers that harbour simultaneously high 53BP1 protein level and BRCA1 promoter hypermethylation and are the putative target population of drugs targeting DNA repair appear to be restricted to a small subgroup of TN tumours.

【 授权许可】

   
2013 Jacot et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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