Triple negative breast cancer (TNBC) is a major breast tumor subtype characterized by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression, and the absence of human epidermal growth factor receptor 2 (HER2) amplification. TNBC patients have a poor clinical outcome with a high rate of recurrence at distant sites. Hence new therapeutic options are urgently needed. We have identified the prototypical BET bromodomain inhibitor JQ1 and BET bromodomain inhibitors (BBDi?s) in general as promising novel therapeutic agents in TNBC. Specifically, we have found that TNBC cell lines are significantly growth inhibited in cell culture by treatment with low nM range BBDi?s, compared with the luminal cell lines, which were relatively resistant. A potential BBDi drug target, BRD4, is highly expressed in TNBCs compared to luminal lines and its downregulation by Tet-inducible shRNA arrests TNBC cell growth. c-Myc, a transcription factor inhibited by JQ1 in some cell types, was also more abundant in TNBC lines compared to luminals, but its protein levels did not correlate with JQ1 response and did not change after JQ1 treatment. In line with the role of BRD4 in transcription restart after G2/M, JQ1 treatment prevented cell cycle re-entry, arrested TNBC cells in early G1, and induced luminal differentiation. The growth of established xenografts derived from TNBC cell lines and patient samples was efficiently inhibited by JQ1 treatment. Based on our preliminary data we hypothesize that (1) the downstream target(s) of BBDi?s critical for G1 re-entry in TNBC is not c-myc and remains to be identified, (2) targeting BRD4 or other bromodomain proteins using BBDi?s alone or in combination with other agents is an active novel therapeutic strategy in TNBC, and (3) BBDi?s will be an active therapy in metastatic TNBC. We propose three specific aims to test these hypotheses:
Aim 1. To define and characterize the drug target and downstream targets of JQ1/BBDi?s in TNBCs.
Aim 2. To conduct a clinical trial to test a BBDi in TNBC patients.
Aim 3. To develop cell lines resistant to BBDi?s and characterize combination therapies to improve therapeutic responses and overcome acquired resistance.

Public Health Relevance

Triple negative breast cancer (TNBC) is the only major breast tumor subtype that lacks targeted therapy and a significant fraction of TNBC patients die of their disease within 5 years of their diagnosis. The proposal aims to validate BET bromodomain inhibitors as novel therapeutic agents in TNBC and define their mechanism of action by conducting preclinical studies and a clinical trial.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Dana-Farber Cancer Institute
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Zhang, Jing; Gao, Xueliang; Schmit, Fabienne et al. (2017) CRKL Mediates p110?-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells. Cell Rep 20:549-557
Heng, Yujing J; Lester, Susan C; Tse, Gary Mk et al. (2017) The molecular basis of breast cancer pathological phenotypes. J Pathol 241:375-391
Rondinelli, Beatrice; Gogola, Ewa; YĆ¼cel, Hatice et al. (2017) EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol 19:1371-1378
Breitkopf, Susanne B; Taveira, Mateus De Oliveira; Yuan, Min et al. (2017) Serial-omics of P53-/-, Brca1-/- Mouse Breast Tumor and Normal Mammary Gland. Sci Rep 7:14503
Thorpe, Lauren M; Spangle, Jennifer M; Ohlson, Carolynn E et al. (2017) PI3K-p110? mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85?. Proc Natl Acad Sci U S A 114:7095-7100
Goel, Shom; DeCristo, Molly J; Watt, April C et al. (2017) CDK4/6 inhibition triggers anti-tumour immunity. Nature 548:471-475
Simond, A M; Rao, T; Zuo, D et al. (2017) ErbB2-positive mammary tumors can escape PI3K-p110? loss through downregulation of the Pten tumor suppressor. Oncogene 36:6059-6066
Spangle, Jennifer M; Roberts, Thomas M; Zhao, Jean J (2017) The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim Biophys Acta 1868:123-131
Liu, Hui; Murphy, Charles J; Karreth, Florian A et al. (2017) Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer. Cancer Discov :
Willis, Nicholas A; Frock, Richard L; Menghi, Francesca et al. (2017) Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 551:590-595

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