@article {625866,
	title = {Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.},
	journal = {Nature},
	year = {2016},
	month = {2016 Jan 6},
	abstract = {Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.},
	issn = {1476-4687},
	doi = {10.1038/nature16508},
	author = {Shu, Shaokun and Lin, Charles Y and He, Housheng Hansen and Witwicki, Robert M and Tabassum, Doris P and Roberts, Justin M and Janiszewska, Michalina and Jin Huh, Sung and Liang, Yi and Ryan, Jeremy and Doherty, Ernest and Mohammed, Hisham and Guo, Hao and Stover, Daniel G and Ekram, Muhammad B and Peluffo, Guillermo and Brown, Jonathan and D{\textquoteright}Santos, Clive and Krop, Ian E and Dillon, Deborah and McKeown, Michael and Ott, Christopher and Qi, Jun and Ni, Min and Rao, Prakash K and Duarte, Melissa and Wu, Shwu-Yuan and Chiang, Cheng-Ming and Anders, Lars and Young, Richard A and Winer, Eric P and Letai, Antony and Barry, William T and Carroll, Jason S and Long, Henry W and Brown, Myles and Shirley Liu, X and Meyer, Clifford A and Bradner, James E and Polyak, Kornelia}
}
