Abstract
Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143-56. ©2017 AACR.
Highlights
Breast cancer and lung cancer are the top two leading causes of cancer deaths in women [1]
We found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo and altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment
Several studies reported the antiproliferative effects of bromodomain inhibitors in breast cancer cell lines and a reduction of tumor mass in mouse xenograft models [48,49,50]
Summary
Breast cancer and lung cancer are the top two leading causes of cancer deaths in women [1]. Even though the survival rates of estrogen receptor–positive (ERþ) breast cancer have gradually improved, primarily because of the benefits of endocrine therapy, the incidence and survival rates for ER–negative (ERÀ) breast cancer have not noticeably shifted over the past 30 years [2]. Lung cancer is responsible for more cancer-related deaths than breast, prostate, colon, and pancreatic cancer combined, and the 5-year survival rates for lung cancer remain a disappointing 18% [1]. New drugs as well as new approaches are greatly needed to reduce both the incidence and mortality of both of these diseases. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).
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