title: MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition.
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.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Dai
authors.initials: D
authors.lastname: Horiuchi
authors.forename: Leonard
authors.initials: L
authors.lastname: Kusdra
authors.forename: Noelle E
authors.initials: NE
authors.lastname: Huskey
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chandriani
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Katelyn J
authors.initials: KJ
authors.lastname: Creasman
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Bazarov
authors.forename: James W
authors.initials: JW
authors.lastname: Smyth
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Davis
authors.forename: Paul
authors.initials: P
authors.lastname: Yaswen
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Esserman
authors.forename: Andrei
authors.initials: A
authors.lastname: Goga
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D018844:Cyclin-Dependent Kinases; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C489427:MYC protein, human; C508053:ERBB2 protein, human