Human breast tumors show great diversity in their morphologies, clinical histories and in their responsiveness to chemotherapy. This wide tumor diversity poses one of the central challenges to the accurate diagnosis and effective treatment of breast cancers. The main focus of my lab is to characterize the diversity of human breast tumors using DNA microarrays, molecular genetics and cell biology to understand the biology of the distinct tumor subtypes that we identified (Perou et al. 2000). We began our characterization of human breast tumors using global gene expression patterns obtained using DNA microarrays (Perou et al. 1999, 2000, Sorlie et al. 2001, 2003) and have identified at least five biologically distinct subtypes of breast tumors. Each subtype is identified by a unique combinatorial pattern of gene expression that is characterized by the high expression of specific sets of genes, and the lack of expression of other sets of genes. We have corroborated these results by demonstrating that these gene expression defined subtypes are predictive of overall patient survival, and relapse free survival (Sorlie et al. 2003, van de Rijn et al. 2002 and Neilson et al. 2004).

The breast tumor "profiling" project is an ongoing project in my lab since it is likely that many hundreds of tumors will ultimately be needed to robustly identify all biologically and clinically relevant tumor subtypes. In addition to our genomic studies of primary human tumors, we are querying our database of tumor derived expression patterns to search for correlations between gene expression patterns and other clinical parameters including response to chemotherapeutics (Troester et al. 2004). Concurrent and complementary to these tumor profiling studies are numerous additional projects, the first of which is a "toxicogenomics" study of the patterns response induced in vitro by chemotherapeutic agents; we have established a panel of cell lines that mimic some of the tumor subtypes and are using these models to elucidate epithelial cell response to therapy. The next project is aimed at determining the cellular and molecular function of specific sets of genes that either define the observed breast tumor subtypes (Finlin et al. 2001, Usary et al. 2004), or which are correlated with resistance to chemotherapy. Our final aim is a epidemiological based analysis of these tumor subtype and our goal here is to identify genes that are predisposition to breast cancer. We have shown that BRCA1 germline mutation carriers overwhelmingly develop basal-like tumors (Sorlie et al. 2003), and hence, other similar predisposition genes must exist. We are using a combination of SNP discovery using candidate gene resequencing and large case-control patient groups (i.e. Carolina Breast Cancer Study) as our population based sample set. Once hundreds of breast tumors have been" profiled" and detailed molecular genetics studies focused on selected genes and signaling pathways have been performed, we hope to develop new predictive clinical tests based upon a deeper understanding of the biology and genetics that are causative of breast tumor formation.