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

• DOI: 10.1084/jem.20111512
• Publication Date: 2012-03-20T04:34:41Z
• Authors: Dai Horiuchi; Leonard Kusdra; Noelle E. Huskey; Sanjay Chandriani; Marc E. Lenburg; Ana Maria Gonzale...; Katelyn J. Creasman; Alexey V. Bazarov; James W. Smyth; Sarah E. Davis; Paul Yaswen; Gordon B. Mills; Laura J. Esserman; Andrei Goga
• Keywords: Biomedical and clinical sciences; Receptor, ErbB-2; Oncology and Carcinogenesis; Immunology; 610; Breast Neoplasms; Medical and Health Sciences; Article; Cell Line; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; ErbB-2; Cell Line, Tumor; Proto-Oncogene Proteins; Breast Cancer; Receptors; Genetics; Animals; Humans; Protein Kinase Inhibitors; Inbred BALB C; Progesterone; Cancer; erbB-2; Mice, Inbred BALB C; 0303 health sciences; Tumor; Biomedical and Clinical Sciences; Bcl-2-Like Protein 11; Health sciences; Membrane Proteins; Prognosis; Estrogen; Xenograft Model Antitumor Assays; Cyclin-Dependent Kinases; 3. Good health; Receptors, Estrogen; Women's Health; Female; Apoptosis Regulatory Proteins; Receptors, Progesterone; Receptor; Signal Transduction

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.