LB58

The identification of pathways responsible for driving the proliferation of basal-like breast cancers

Dorota Tkocz, Niamh Buckley, Paul Mullan

Queens University Belfast, UK

Background
Numerous microarray studies have revealed that breast cancers can be divided into 5 subtypes, namely luminal A, luminal B, HER2, normal-like and basal-like. Basal-like breast cancers are the subtype with the worst prognosis and are unresponsive to endocrine or Herceptin therapies. To date no oncogene or pathway has been found to be responsible for driving proliferation of this subtype. However, basal-like breast cancers share many features with BRCA1 mutant tumours suggesting that a defect in BRCA1 function may be a causative event.

Results
By comparing datasets from a number of published microarray studies we have generated a siRNA library targeting 32 genes known to be overexpressed in basal-like and BRCA1 mutant breast cancer. We have used this library in HCC1937 (BRCA1 mutant) and MDA468 (low BRCA1) to assess the role of these candidate genes in cell proliferation. Five of these genes consistently showed growth inhibition following siRNA knockdown and these were validated as BRCA1 targets.

We are currently performing promoter analyses of these target genes using cell models with either BRCA1 reconstitution or stable shRNA knockdown. We will identify the minimal promoter regions responsive to BRCA1 and confirm using site directed mutagenesis and chromatin immunoprecipitation (ChIP) studies. Ultimately we aim to identify and validate genes essential for the proliferation of basal-like breast cancers which represent targets for future therapies.

Conclusion
We have identified transcriptional targets of BRCA1 which may play a role in driving basal-like breast cancer. We aim to identify the mechanism of their repression in normal breast cells and to identify novel therapeutic targets.