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.
Highlights
Proteins are epigenetic “readers” that recognize acetylated histones and mark areas of the genome for transcription
Similar effects as JQ1 were observed with two additional BET inhibitors (BETi), I-BET151 and I-BET762 (Fig. 1, D and E), indicating JQ1-induced growth suppression was due to inhibition of bromodomain and extraterminal (BET) protein function and not off-target effects
While BETi have previously been shown to reduce invasiveness of Triple-negative breast cancer (TNBC) cells, in vitro (14), and inhibit tumor growth in xenograft models (13,14,16), the utility in different subtypes of TNBC and the mechanism by which BETi elicit their effects on growth has not been previously established
Summary
Proteins are epigenetic “readers” that recognize acetylated histones and mark areas of the genome for transcription. MDA-MB-231 and HCC38 cells are amongst the most growth-suppressed, yet MYC protein expression is unchanged in response to JQ1 treatment.
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