Abstract：
:Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. Although BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks an SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi. Cancer Res; 77(19); 5395-408. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Sahni JM,Gayle SS,Webb BM,Weber-Bonk KL,Seachrist DD,Singh S,Sizemore ST,Restrepo NA,Bebek G,Scacheri PC,Varadan V,Summers MK,Keri RAdoi
10.1158/0008-5472.CAN-17-1571subject
Has Abstractpub_date
2017-10-01 00:00:00pages
5395-5408issue
19eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-1571journal_volume
77pub_type
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