23P - Alternate epigenetic mechanism for the repression of BRCA1 in sporadic breast cancers mediated by miR182

Date 08 May 2014
Event IMPAKT 2014
Session Welcome reception and Poster Walk
Topics Breast Cancer
Translational Research
Presenter Aruna Korlimarla
Citation Annals of Oncology (2014) 25 (suppl_1): i8-i16. 10.1093/annonc/mdu066
Authors A. Korlimarla1, J.S. Prabhu1, J. Remacle1, U. Raja1, B.S. Srinath2, T.S. Sridhar1
  • 1Molecular Medicine, St John's Research Institute, 560034 - Bangalore/IN
  • 2Surgical Oncology, Sri Shankara Cancer Hospital and Research Center, 560004 - Bangalore/IN

Abstract

Introduction:

BRCA1 dysfunction in sporadic breast cancer leading to genomic instability, and the clinical resemblance to familial germ-line BRCA1 mutated breast cancers has been termed “BRCAness”. The proven mechanisms for diminished BRCA1 function in sporadic BCs include promoter methylation and transcriptional repression by ID4. Moskwa et al., have shown that miR182 selectively down regulates BRCA1 expression in cell lines with defective HR and NHEJ. Here we report the quantitative estimation of miR182 in primary sporadic breast cancers and found it to be inversely correlated with the transcript and protein levels of BRCA1.

Methods:

245 surgically excised primary breast tumors, including 60 triple negative breast cancers (TNBC) were used in this study. Relative transcript abundances for BRCA1, ID4 and and miR182 were assessed using a TaqMan qRT-PCR. The 60 TNBCs and a control set of 40 HR +, HER2 negative tumors, were examined for the presence of BRCA1 protein by IHC with the MS110 clone. A modified H score with a cut-off of 10% of cells with nuclear staining was the criterion for positivity.

Results:

In all 245 tumors we noted an inverse correlation between the expression levels of miR182 and BRCA1 transcripts with a coefficient (r2) of 0.1. Subclassification based upon receptor status revealed average expression of miR182 was 3 fold higher in TNBCs as compared to the HR +, HER2 negative sub-class (p < 0.001). 34/100 samples had no nuclear staining for BRCA1. The inverse correlation between miR182 and BRCA1 transcripts was mirrored in the BRCA1 protein as well. The samples that lacked nuclear BRCA1 were predominantly TNBCs. While only 60% of the 100 tumors were TNBCs, 82% (28/34) of the specimens which lacked nuclear BRCA1 were TNBCs. The epigenetic silencing of BRCA1 by miR-182 worked in concert with the transcriptional repression of BRCA1 by ID4 in a quarter of the patients.

Conclusion:

A decade after the definition of BRCAness, it has remained an interesting concept with minimal adoption into routine clinical practice. This is partly due to the lack of validated molecular assays. The approach outlined above, that combines quantitative estimation of proven repressors will help expedite the wider clinical identification of this sub-class, which has important therapeutic utility, particularly for TNBCs.

Disclosure:

All authors have declared no conflicts of interest.