Background: Breast cancer is the most prevalent malignancy diagnosed in women in the Western world. Recent gene expression studies have divided breast cancer into multiple subtypes. Basal-like breast cancer (BBC) is one subtype of particular interest as it is associated with poor patient outcome and shows association with BRCA1 mutations. BBC is characterized by expression of the stratified epithelial marker cytokeratin 5 and absent expression of estrogen receptor (ER), progesterone receptor, (PR), and, Her2Neu. BBC typically shows high grade histology, behaves aggressively and the absence of ER and Her2Neu expression limits the therapeutic options. Objective: The key objectives of this study are (1) to identify the causal genetic events responsible for the signature expression profile of BBC and (2) to identify biological pathways disrupted in BBC tumourigenesis. Materials and Methods: Ten cases with characteristics consistent with BBC were identified from a collection of archived breast cancer samples at Vancouver General Hospital. Specimens were microdissected from paraffin blocks to isolate malignant cells. This yielded sufficient quantities of DNA for whole genome analysis for DNA copy number changes. Tumour genomes were analyzed at high resolution using a newly developed whole genome tiling path array of 32,433 overlapping human bacterial artificial chromosome (BAC) clones spanning the entire human genome. Results: The BBC genome profiles obtained reveal recurrent gains and losses of DNA segments. Alignment of multiple genome profiles revealed that several of these genetic alterations occurred in multiple cases, including changes within the chromosomal arms of 6p24, 8p23, 10p15 and 20q13. Array-based results were verified by fluorescence in situ hybridization (FISH) analysis against Breast Tissue MicroArray (TMA). Conclusion: We have identified multiple novel recurrent regions of genetic alterations in BBC. Such alterations may harbour tumour suppressor or oncogenes. Comparison or integration of genomic and gene expression data sets will facilitate the discovery of genes and pathways disrupted that are crucial to the development of BBC.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]