Aberrant MYC expression is a common oncogenic event in human cancer. Paradoxically, MYC can either drive cell cycle progression or induce apoptosis. The latent ability of MYC to induce apoptosis has been termed "intrinsic tumor suppressor activity", and reactivating this apoptotic function in tumors is widely considered a valuable therapeutic goal. As a transcription factor, MYC controls the expression of many downstream targets and for the majority of these it remains unclear whether or not they play direct roles in MYC function. To identify the subset of genes specifically required for biological activity, we conducted a screen for functionally important MYC targets, and identified BAG1, which encodes a pro-survival chaperone protein. Expression of BAG1 is regulated by MYC in both a mouse model of breast cancer and in transformed human cells. Remarkably, BAG1 induction is absolutely required for protecting cells from MYC-induced apoptosis. Ultimately, the synthetic lethality we have identified between MYC overexpression and BAG1 inhibition, establishes a new pathway that might be exploited to reactivate the latent apoptotic potential of MYC as a cancer therapy. The studies proposed here will define the parameters of this new pathway and establish pre- clinical evidence of its utility as a therapeutic target.
As a universal hallmark of human cancer, MYC oncogene activation represents a theoretically valuable target for therapy. We have identified the BAG1 gene as a novel and critical component of the MYC pathway that can be targeted to selectively induce cancer cell death.
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