Our goal is to identify and analyze the growth regulatory pathways responsible for neoplasia of the breast. Specifically we would like to investigate the molecular basis of the initiation and progression of breast cancer.

To identify molecular alterations involved in the initiation and progression of breast carcinomas we are analyzing the global gene expression profiles of normal mammary epithelial cells, and in situ, invasive and metastatic breast carcinomas using Serial Analysis of Gene Expression (SAGE). Using this approach we identified sets of genes expressed only or most abundantly in a specific stage of breast tumorigenesis or in a certain subtype of tumors through the pair-wise comparison and by hierarchical clustering analysis of these SAGE libraries. We found that the most dramatic and consistent phenotypic change occurred at the normal to in situ carcinoma transition. This observation, combined with the fact that many of the genes involved encode secreted, cell non-autonomous factors, implies that the normal epithelium to in situ carcinoma transition may be the most promising target for cancer prevention and treatment.

Identification of molecular markers in DCIS

Ductal carcinoma in situ DCIS is believed to be the true precursor of invasive ductal carcinoma, therefore studies aimed at characterizing the molecular alterations underlying DCIS should not only facilitate its prognostication, prevention and treatment, but could also reduce the incidence of potentially lethal invasive cancers. We propose to identify clinically useful molecular markers in DCIS using the combination of comprehensive gene expression profiling (SAGE) and tissue microarrays. We plan to identify transcripts that define biologically and potentially clinically meaningful subgroups of DCIS, and determine whether any of these transcripts can help predict local recurrence and/or progression to invasive cancer following surgical resection. The identification of such candidate genes is likely to further our understanding of the pathophysiology of DCIS lesions and can be the basis of future studies aimed at the development of novel diagnostic and therapeutic tools.

Identification of candidate genes for the initiation or progression of breast tumors

In addition to molecular marker discovery, we also use the SAGE data to identify candidate genes that play an important functional role in the initiation or progression of breast tumors. One of these genes, HIN-1 (High In Normal-1) appears to be particularly interesting due to multiple reasons. First, HIN-1 expression is significantly down regulated in 94% of human breast carcinomas and in 95% of pre-invasive lesions such as ductal and lobular carcinoma in-situ. Second, the expression of HIN-1 is silenced by methylation in the majority of breast cancer cell lines (>90%) and primary tumors (74%). Third, HIN-1 is a novel cytokine with no significant homology to known proteins. Last, reintroduction of HIN-1 into breast cancer cells inhibits cell growth. These results indicate that HIN-1 is a candidate tumor suppressor gene that is inactivated at high frequency in the earliest stages of breast tumorogenesis. Since HIN-1 is inactivated in pre-invasive tumors, such as DCIS and LCIS, the elimination of the HIN-1 signaling pathway may be a pivotal step in the initiation of breast tumorogenesis. In addition, the methylation of HIN-1 in a high fraction of early-stage tumors makes it an excellent molecular marker for early detection. Moreover, since HIN-1 is a cytokine and breast carcinomas appear to express a putative HIN-1 receptor, the HIN-1 signaling pathway may provide a new target for cancer prevention and treatment. Currently we are focusing on the further characterization of HIN-1 including the identification of its signaling receptor.