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.
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.
|Spangle, Jennifer M; Dreijerink, Koen M; Groner, Anna C et al. (2016) PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer. Cell Rep 15:2692-704|
|Montaser-Kouhsari, Laleh; Knoblauch, Nicholas W; Oh, Eun-Yeong et al. (2016) Image-guided Coring for Large-scale Studies in Molecular Pathology. Appl Immunohistochem Mol Morphol 24:431-5|
|Morganella, Sandro; Alexandrov, Ludmil B; Glodzik, Dominik et al. (2016) The topography of mutational processes in breast cancer genomes. Nat Commun 7:11383|
|Cheng, H; Liu, P; Ohlson, C et al. (2016) PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 35:2961-70|
|Choi, Young Eun; Meghani, Khyati; Brault, Marie-Eve et al. (2016) Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer. Cell Rep 14:429-39|
|Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6|
|Wang, Q; Liu, P; Spangle, J M et al. (2016) PI3K-p110Î± mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 35:3607-12|
|Nik-Zainal, Serena; Davies, Helen; Staaf, Johan et al. (2016) Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534:47-54|
|Smid, Marcel; RodrÃguez-GonzÃ¡lez, F GermÃ¡n; Sieuwerts, Anieta M et al. (2016) Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration. Nat Commun 7:12910|
|Johnson, Shawn F; Cruz, Cristina; Greifenberg, Ann Katrin et al. (2016) CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep 17:2367-2381|
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