Cancer and normal development share many properties. During normal development, genes are activated that stimulate proliferation, migration, invasion, vascularization, and that alter cell survival. These gene products are often lost once organ development is complete. In cancer, many developmental genes are re-activated, stimulating the aforementioned processes out of context. The Six1 gene encodes a transcription factor that induces the expression of a large number of genes that are involved in the proliferation, survival, migration, and invasion of cells during embryonic development. In most tissues, Six1 expression is lost once development is complete. However, Six1 is reactivated in many breast cancers, where as many as 90% of metastatic tumors overexpress the gene. Six1 plays a role in both tumor initiation and metastasis of breast cancers, and its inhibition dramatically diminishes both tumor cell proliferation and metastasis in a number of mouse cancer models. Because Six1 is expressed during embryogenesis, lost in most adult tissues, and re-expressed in tumors, we believe it is an ideal drug target whose inactivation will inhibit tumor cell proliferation and metastasis with limited side effects.

Our goal in this proposal is to lay the foundation for developing novel, tumor-specific chemotherapeutic agents for breast cancer. This will be accomplished by coupling the expertise of a cancer/molecular biologist with a structural biologist/biochemist. Within the proposal, we will identify multiple avenues for targeting the Six1 transcriptional complex, and use an innovative rational drug design and complementary high throughput screeing (HTS) approach to identify small molecule inhibitors of the Six1 complex. The Six1 transcriptional complex has never before been clinically targeted, but its inhibition would be expected to inhibit both tumor cell proliferation and metastasis, while sparing normal cells. Such a target is badly needed in breast cancer, where many of the currently used therapies have serious side effects. This research is expected to benefit 50% of breast cancer patients with primary breast tumors and 90% with metastatic tumors, as Six1 is expressed in the aforementioned percentage of breast cancer cases. We project to have lead compounds targeting Six1 within five years. The DOD Synergistic IDEA grant will greatly facilitate our efforts in generating lead compounds as soon as possible.