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.

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

“…As an intermediary proof-ofconcept, we recently showed that ALA-PDT suppression of mouse-borne human breast tumor xenografts was substantially augmented by administration of 1400W or GW274150, whereas no significant effect was observed on control tumor growth (52). Consistently, iNOS protein in tumor samples was strongly upregulated after ALA-PDT, and NO-derived NO 2 -levels were also elevated relative to control levels -and in 1400W-inhibitable fashion (53). However, it was apparent from our previous in vitro and in vivo studies that the modulating effects of iNOS enzyme inhibitors (e.g.…”

“…However, it was apparent from our previous in vitro and in vivo studies that the modulating effects of iNOS enzyme inhibitors (e.g. increased PDT cytotoxicity or decreased survivor aggressiveness) were far from maximal at relatively high inhibitor concentrations or dosages (24)(25)(26)53). This prompted us to ask whether possible suppression of iNOS expression with a BET bromodomain inhibitor such as JQ1 might be more effective than inhibition of expressed iNOS activity.…”

“…10C). Strong induction of p21 by JQ1 has been reported for several other cell lines (47,53,54). Such induction could promote cell death through arrest of cell cycle progression.…”

Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors

“…RNA analysis was performed as previously described (12) using the following TaqMan Gene Expression Assays (Thermo Fisher): CCNB1 (Hs01030099_m1); E2F2 (Hs00231667_m1); E2F8 (Hs00226635_m1); FOXM1 (Hs01073586_m1); KIF2C (Hs00901710_m1); KIF20A (Hs00993573_m1); LIN9 (Hs00542748_m1); LIN37 (Hs00375230_m1); MYBL2 (Hs00942543_m1); PLK1 (Hs00983227_m1); GAPDH (Hs02758991_g1).…”

“…We and others have recently reported that bromodomain and extraterminal protein inhibitors (BETi) are efficacious in multiple models of TNBC (9–13). We further discovered that BETi induce the formation of large, multinucleated cells followed by apoptosis and senescence, suggesting these drugs cause mitotic catastrophe (12). BETi selectively target the BET family of epigenetic readers by binding to the bromodomain pockets of BET proteins (BRD2, BRD3, BRD4, and BRDT).…”