title: Bromodomain and Extraterminal Protein Inhibition Blocks Growth of Triple-negative Breast Cancers through the Suppression of Aurora Kinases.
abstract: Bromodomain and extraterminal (BET) proteins are epigenetic "readers" that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer, and BET protein inhibitors (BETi) are efficacious in many preclinical cancer models. However, the drivers of response to BETi vary depending on tumor type, and little is known regarding the target genes conveying BETi activity in triple-negative breast cancer (TNBC). Here, we show that BETi repress growth of multiple in vitro and in vivo models of TNBC by inducing two terminal responses: apoptosis and senescence. Unlike in other cancers, response to BETi in TNBC is not dependent upon suppression of MYC Instead, both end points are preceded by the appearance of polyploid cells caused by the suppression of Aurora kinases A and B (AURKA/B), which are critical mediators of mitosis. In addition, AURKA/B inhibitors phenocopy the effects of BETi. These results indicate that Aurora kinases play an important role in the growth suppressive activity of BETi in TNBC. Elucidating the mechanism of response to BETi in TNBC should 1) facilitate the prediction of how distinct TNBC tumors will respond to BETi and 2) inform the rational design of drug combination therapies.
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Sahni
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Gayle
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Kristen L Weber
authors.initials: KL
authors.lastname: Bonk
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Leslie Cuellar
authors.initials: LC
authors.lastname: Vite
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Yori
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Bryan
authors.initials: B
authors.lastname: Webb
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Erika K
authors.initials: EK
authors.lastname: Ramos
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Darcie D
authors.initials: DD
authors.lastname: Seachrist
authors.affiliation: the Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas 77030, and.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.affiliation: the Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas 77030, and.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: the Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: From the Departments of Pharmacology and keri@case.edu.|Genetics and Genome Sciences and General Medical Sciences-Oncology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Keri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins
keywords: Aurora kinase; anticancer drug; apoptosis; breast cancer; bromodomain-containing protein 4 (BRD4); cellular senescence; inhibition mechanism