Genomic Discovery of Novel Oncogenes and Tumor Suppressor Genes in Human Breast Cancer

Abstract

Advances in genomic technologies have facilitated the identification of novel tumor markers that predict prognosis. By making use of multiple genomic technologies, we describe here two methods that lead to the discovery of such markers in breast cancer:

We sought novel targetable oncogenes by identifying secretory factors where overexpression is associated with cancer recurrence in multiple cohorts. Candidates were then assessed for phenotypic consequences by altering candidate gene expression in vitro. The top candidate, serine protease inhibitor Kazal-type 1 (SPINK1) was found to induce invasion, protect cells from apoptosis, and induce metastatic potential of cancer cells in mice. Downstream analysis revealed that SPINK1 caused resistance to apoptosis through the reduction of transcription and repressed activity of Bcl-2 in cancer cells.

In a complementary project, we sought to identify candidate tumor suppressor genes in genomic regions that have exhibited a decrease in copy number and evidence for reduction to homozygosity in MCF-7. Genes in these regions coupled with silencing of transcription were identified. Based on association studies with patient prognosis, semaphorin 6D (SEMA6D) was discovered to function as a key player in a closely integrated tumor suppressor network, regulating cell death in breast cancer cells.