Abstract C23: Therapy of triple-negative breast tumors by targeting the MYC oncogene pathway

Abstract

Abstract Human breast cancers that lack expression of the estrogen and progesterone nuclear receptors and with low HER2 expression are known as “gtriple-negative” tumors. These are amongst the most aggressive breast cancers and no targeted therapeutics exists for this subclass of human tumors. MYC is a proto-oncogene transcription factor that plays a key role in cell cycle transition of mammalian cells. Increased expression of MYC is estimated to occur in ∼ 20–50% of human breast cancers. Genomic amplification of the MYC locus, 8q24, is correlated with decreased patient survival, and MYC-over-expression in breast cancer cells has been associated with a resistance to anti-hormonal therapies that seek to inhibit ER signaling. Furthermore, MYC has recently been shown to be one of the genes unique to high-grade mammary tumors. Thus, these prior studies suggest that the level of MYC expression might be useful as a biomarker and that the inhibition of MYC function may be a useful therapeutic approach against this difficult-to-treat type of breast cancer. However, while MYC is strongly implicated in breast tumorigenesis, no direct small molecule inhibitors of its transcriptional activity are available in clinical practice. An alternative approach to directly inhibiting MYC is to find “synthetic-lethal” combinations that selectively kill those cells with elevated MYC levels without affecting normal cells. The term “synthetic-lethality” refers to a genetic context in which a mutation in a gene, which itself does not cause lethality, can cause lethality when combined with a mutation in another gene. Using engineered cells, we have previously demonstrated that inhibiting cyclin-dependent kinase 1 (CDK1) can kill cells that over-express MYC. We have now used a panel of breast cancer cell lines established from human patients to show that (1) those breast cancers that are receptor-negative have significantly higher levels of MYC protein, (2) that the MYC pathways are critical for the survival and proliferation of this tumor subset, (3) CDK1 inhibition in triple-negative breast cancer cells results in the initiation of apoptosis mediated by mitochondria-dependent intrinsic pathway, and that (4) this apoptotic event is specifically achieved by altering the balance between pro-survival and pro-apoptotic members of the Bcl-2 family proteins. Our results present a novel treatment strategy for “triple-negative” breast cancers by targeting the MYC pathways via CDK inhibitors. Citation Information: Cancer Res 2009;69(23 Suppl):C23.