Grant: Foundation Grant

Breast cancer progression involves multiple events including the activation of dominant-acting oncogenes and the loss of specific tumor suppressor genes. These events can occur through well-established genetic mechanisms, such as mutation and chromosomal instability, or through more recently identified epigenetic alterations involving processes such as DNA methylation and chromatin modification. Pharmacological inhibition of activated oncogenes is the basis for rationally designed "targeted therapies" that specifically inhibit the growth and survival of tumor cells. However, while many such drugs are now clinically approved, they are plagued by the emergence of resistance in the vast majority of patients. Thus, breast cancer still remains a leading cause of cancer morbidity in women. This foundation proposal will focus on the use of Genetic Engineered Mouse Models (GEMMs) of the different human breast cancer subtypes to elucidate the molecular mechanism underlying breast cancer progression, to test and optimize treatment strategies and to understand mechanisms of resistance to conventional breast cancer therapeutics. Under the aegis of this foundation proposal, we plan to validate molecular insights derived from these GEMMs in the primary human breast cancer setting. Ultimately, this approach will lead to the development of novel combinational strategies to treat and manage breast cancers and decrease breast cancer morbidity.