DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine
Jia Yu, … , Matthew P. Goetz, Liewei Wang
Jia Yu, … , Matthew P. Goetz, Liewei Wang
Published April 30, 2018
Citation Information: J Clin Invest. 2018;128(6):2376-2388. https://doi.org/10.1172/JCI97924.
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Research Article Oncology

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2′-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor–associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.

Authors

Jia Yu, Bo Qin, Ann M. Moyer, Somaira Nowsheen, Tongzheng Liu, Sisi Qin, Yongxian Zhuang, Duan Liu, Shijia W. Lu, Krishna R. Kalari, Daniel W. Visscher, John A. Copland, Sarah A. McLaughlin, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard J. Gray, Zhenkun Lou, Vera J. Suman, Richard Weinshilboum, Judy C. Boughey, Matthew P. Goetz, Liewei Wang

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Figure 2

PDXs expressing high levels of DNMTs showed greater sensitivity to decitabine treatment.

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PDXs expressing high levels of DNMTs showed greater sensitivity to decit...
(A) Schematic outline of decitabine treatment for the PDX tumors. Small pieces of passage 2 tumors were injected s.c. into the back flanks of SCID mice (n = 6–7 respectively). Drug was administered i.p. and started when the tumors grew to 150–200 mm3. Mice were treated with decitabine for 4 days per cycle, followed by 3 days of recovery. (B) Tumor-response curve for PDX tumors. Mice bearing passage 3 breast cancer PDX tumors were treated with either vehicle (blue) or 5 mg/kg decitabine (pink) according to the time schedule described in A. Tumors were measured twice weekly. Data represent mean tumor volume ± SEM for all tumors at each indicated day (n = 6–7 mice respectively). PDX line ID MCD numbers correspond to MCD-IDs shown in Figure 1D. Tumors were harvested at the time when experiments were terminated, and tumor weight was measured. Data represent mean ± SEM. **P < 0.01; ***P < 0.001, 2-tailed t test.