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J Exp Med. 2012 Apr 9;209(4):679-96. doi: 10.1084/jem.20111512. Epub 2012 Mar 19.

MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition.

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  • 1Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

Abstract

Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well as altered expression of MYC regulatory genes, resulting in increased activity of the MYC pathway. In primary breast tumors, MYC signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. We exploit the increased MYC expression found in triple-negative breast cancers by using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. CDK inhibition effectively induced tumor regression in triple-negative tumor xenografts. The proapoptotic BCL-2 family member BIM is up-regulated after CDK inhibition and contributes to this synthetic-lethal mechanism. These results indicate that aggressive breast tumors with elevated MYC are uniquely sensitive to CDK inhibitors.

PMID:
22430491
[PubMed - indexed for MEDLINE]
PMCID:
PMC3328367
Free PMC Article

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