Metabolic reprogramming is a major mechanism of fueling cancer cell growth and proliferation. However, how tumor metabolism is altered to confer therapeutic resistance is poorly understood. Gene expression profiling of tamoxifen sensitive and resistant breast cancer cells revealed that transition to the resistance was associated with a specific expression reprogramming of genes involved in glucose/energy metabolism, which was accompanied by aberration of specific epigenetic regulators such as the histone methyltransferase NSD2/MMSET/WHSC1. In cell and xenograft tumor models, NSD2 overexpression alone was sufficient to confer tamoxifen resistance. Analysis of clinical specimens indicates that NSD2 was a strong predictive factor for early relapse of tamoxifen therapy. NSD2 wild type, but not its methylase-defective mutant form, coordinately stimulated the expression and enzymatic activity of HK2, TIGAR and G6PD and strongly augmented the pentose phosphate pathway (PPP) production of NADPH for ROS reduction and survival of tamoxifen treated cells and tumors. Further mechanistic studies demonstrated that elevated NSD2 stimulates the metabolic gene expression through H3K36 methylation at the target chromatin. Pharmacological targeting aberrant NSD2 by DZNeP, an S-adenosylhomocysteine (AdoHcy) hydrolase inhibitor, effectively blocked the growth of tamoxifen-resistant tumor. The study reveals a novel mechanism of cancer metabolic reprogramming and suggests targeting the key metabolic re-programmer as a viable option for effective treatment of endocrine resistant tumors.

Note: This abstract was not presented at the meeting.

Citation Format: June X. Zou, Junjian Wang, Zhijian Duan, Hongwu Chen, Hsing-Jien Kung, Xinbin Chen, Leigh C. Murphy, Alexander Borowsky. Metabolic reprogramming by an epigenetic mechanism in endocrine therapy resistance of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2433. doi:10.1158/1538-7445.AM2014-2433