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  • 1
    Publication Date: 2016-01-07
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shu, Shaokun -- Lin, Charles Y -- He, Housheng Hansen -- Witwicki, Robert M -- Tabassum, Doris P -- Roberts, Justin M -- Janiszewska, Michalina -- Huh, Sung Jin -- Liang, Yi -- Ryan, Jeremy -- Doherty, Ernest -- Mohammed, Hisham -- Guo, Hao -- Stover, Daniel G -- Ekram, Muhammad B -- Peluffo, Guillermo -- Brown, Jonathan -- D'Santos, Clive -- Krop, Ian E -- Dillon, Deborah -- McKeown, Michael -- Ott, Christopher -- Qi, Jun -- Ni, Min -- Rao, Prakash K -- Duarte, Melissa -- Wu, Shwu-Yuan -- Chiang, Cheng-Ming -- Anders, Lars -- Young, Richard A -- Winer, Eric P -- Letai, Antony -- Barry, William T -- Carroll, Jason S -- Long, Henry W -- Brown, Myles -- Liu, X Shirley -- Meyer, Clifford A -- Bradner, James E -- Polyak, Kornelia -- CA080111/CA/NCI NIH HHS/ -- CA103867/CA/NCI NIH HHS/ -- CA120184/CA/NCI NIH HHS/ -- CA168504/CA/NCI NIH HHS/ -- P50 CA168504/CA/NCI NIH HHS/ -- R01 CA103867/CA/NCI NIH HHS/ -- England -- Nature. 2016 Jan 21;529(7586):413-7. doi: 10.1038/nature16508. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; Princess Margaret Cancer Center/University Health Network, Toronto, Ontario M5G1L7, Canada. ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G2M9, Canada. ; Harvard University, Cambridge, Massachusetts 02138, USA. ; Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK. ; Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. ; Broad Institute, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735014" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-06-02
    Description: Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ER + ) breast cancers treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA sequencing in 68 ER + breast cancers from patients treated with preoperative letrozole (median, 7 months). Results: Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC 〉 1, FDR 〈 0.03) in letrozole-resistant tumors with transcription-binding data showed significant overlap with 20 E2F4-regulated genes ( P = 2.56E–15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long-term estrogen-deprived ER + breast cancer cells, palbociclib also downregulated all 20 E2F4 target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant-treated ER + tumors in METABRIC. Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER + breast cancer cells and in patients' ER + tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER + breast cancer who fail to respond to preoperative estrogen deprivation. Clin Cancer Res; 24(11); 2517–29. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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