An epigenomic approach to therapy for tamoxifen-resistant breast cancer

Feng, Qin; Zhang, Zheng; Shea, Martin J.; Creighton, Chad J.; Coarfa, Cristian; Hilsenbeck, Susan G.; Lanz, Rainer B.; He, Bin; Wang, Lei; Fu, Xiaoyong; Nardone, Agostina; Song, Yuanlin; Bradner, James E.; Mitsiades, Nicholas; Mitsiades, Constantine S.; Osborne, C. Kent; Schiff, Rachel; O’Malley, Bert W.

doi:10.1038/cr.2014.71

Cited by 161 publications

(182 citation statements)

References 40 publications

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“…The fact that the elevated function of each of the NSD2 target genes is required for NSD2-mediated therapeutic resistance emphasizes the importance of the coordinated nature of NSD2 function in metabolic reprogramming. Recently, NSD2 was implicated in regulation of ERα gene expression [19]. Consistent with this, we also found that NSD2 knockdown decreased ERα expression in tamoxifensensitive breast cancer cells.…”

Section: Discussionsupporting

confidence: 77%

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Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

et al. 2016

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A B S T R A C TMetabolic reprogramming such as the aerobic glycolysis or Warburg effect is well recognized as a common feature of tumorigenesis. However, molecular mechanisms underlying metabolic alterations for tumor therapeutic resistance are poorly understood. Through gene expression profiling analysis we found that histone H3K36 methyltransferase NSD2/MMSET/WHSC1 expression was highly elevated in tamoxifenresistant breast cancer cell lines and clinical tumors. IHC analysis indicated that NSD2 protein overexpression was associated with the disease recurrence and poor survival. Ectopic expression of NSD2 wild type, but not the methylase-defective mutant, drove endocrine resistance in multiple cell models and xenograft tumors. Mechanistically, NSD2 was recruited to and methylated H3K36me2 at the promoters of key glucose metabolic enzyme genes. Its overexpression coordinately up-regulated hexokinase 2 (HK2) and glucose-6-phosphate dehydrogenase (G6PD), two key enzymes of glycolysis and the pentose phosphate pathway (PPP), as well as TP53-induced glycolysis regulatory phosphatase TIGAR. Consequently, NSD2-driven tamoxifen-resistant cells and tumors displayed heightened PPP activity, elevated NADPH production, and reduced ROS level, without significantly altered glycolysis. These results illustrate a coordinated, epigenetic activation of key glucose metabolic enzymes in therapeutic resistance and nominate methyltransferase NSD2 as a potential therapeutic target for endocrine resistant breast cancer.© 2016 Elsevier Ireland Ltd. All rights reserved. IntroductionTumor growth involves reprogrammed glucose metabolism, featured in aerobic glycolysis, to meet the high demand of glycolytic intermediates for biosynthesis of macromolecules. The pentose phosphate pathway (PPP) is a major cellular source of NADPH, in addition to its supply of precursors for nucleotide biosynthesis. Deregulated PPP has been suggested to promote cancer progression and therapy resistance [1]. The activities of PPP can be decreased by p53, as well as being hyperactivated by oncogenic signaling [2][3][4][5]. Functioning as a fructose-2,6-bisphosphatase (F2,6bPase), TIGAR (TP53-induced glycolysis and apoptosis regulator) can enhance glucose carbon flux to the PPP by dampening glycolysis and is required for the development of intestinal adenomas [6][7][8][9]. As a glycolysis modulator, TIGAR was shown to localize in cytoplasm and associate with mitochondria in complex with the hexokinase HK2 in response to hypoxia [7]. HK2, one of the hexokinases that catalyze the first and rate-limiting step of glucose metabolism, is highly expressed in most tumor cells. HK2 plays a pivotal role in diversion of glucose into pathways such as the PPP for enhanced anabolic metabolism required for tumor growth [10,11]. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the PPP and plays a key role in production of NADPH, the major cellular source of reducing power. However, the mechanism of how the different metabolic genes are coordinately regulat...

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Section: Discussionsupporting

confidence: 77%

“…NSD2 can also act as a coactivator of NF-κB in mediating cytokinedependent autocrine loop for cancer cell growth and survival [15]. One recent study showed that NSD2 could directly regulate estrogen receptor ERα expression in breast cancer cells [19].…”

Section: Introductionmentioning

confidence: 99%

Reprogramming metabolism by histone methyltransferase NSD2 drives endocrine resistance via coordinated activation of pentose phosphate pathway enzymes

et al. 2016

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“…Although molecular typing and screening in recent years have provided an effective method for choosing the most sensitive candidates for endocrine therapy, a considerable number of patients exist that are not sensitive to endocrine therapy (17,18). Therefore, further investigation of the specific indicators is necessary for improving the efficacy of endocrine treatment.…”

Section: Discussionmentioning

confidence: 99%

Analysis of factors affecting endocrine therapy resistance in breast cancer

Zhang

Chen

2015

Oncology Letters

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Abstract. The present study aimed to identify the factors involved in the resistance to endocrine therapy in breast cancer (BC) patients with a positive estrogen receptor status via the collection of clinical, pathological and immunohistochemical indices. A retrospective survey was performed in patients who experienced the relapse and metastasis of BC between November 2007 and March 2013. A total of 45 patients were enrolled, and the observational duration was 7-84 months. The Kaplan-Meier method was used to create a survival curve, while the log-rank test was used to analyze the survival curve and the Cox regression analysis was used to investigate the associated factors contributing to the resistance to endocrine therapy. Univariate analysis showed that the age of onset, the use of radiotherapy, the endocrine treatment program, and the expression levels of progesterone receptor (PR) and CerbB2 affected the impact of endocrine treatment. The Cox regression analysis indicated that the age of onset, the use of radiotherapy, and the expression levels of PR and CerbB2 affected the disease-free survival time after endocrine therapy. A young age of onset, not receiving radiotherapy, a low expression level of PR and a high expression level of CerbB2 were the risk factors involved in the resistance to endocrine therapy in patients with BC. IntroductionBreast cancer (BC) is a common malignancy that is a serious threat to the health of women. It has been reported that ~1.5 million women are diagnosed with BC annually in the world and that nearly 0.5 million succumb to this disease (1). With accumulating studies on BC, the therapeutic schemes for BC have become much more mature, evolving from the initial local excision to current surgery-based comprehensive treatments, including radiotherapy, chemotherapy, endocrine therapy, biological immune therapy and molecular-targeted therapy.The estrogen receptor (ER) is often found in BC and this cancer is consequently labeled as ER-positive (ERP). Furthermore, as the occurrence and development of BC is so closely associated with the expression of the ER (2), endocrine therapy has been widely used as an effective therapeutic method. In the past few decades, endocrine therapeutic drugs have significantly improved the clinical outcomes of BC patients, as well as their quality of life (3,4). Recently, two multi-center, large-scale, prospective clinical trials further established the positive effect of endocrine therapy in BC treatment (5,6).However, with the extension of endocrine treatment, certain studies found that a few BC patients showed resistance to endocrine therapy. The clinical data indicated that although there were BC-ERP patients who were suitable for endocrine therapy, ~30% of BC-ERP patients exhibited resistance to endocrine drugs in the early stages of treatment (primary resistance), and ~40% BC-ERP of patients showed the effectiveness of endocrine therapy prior to exhibiting gradually reduced sensitivity or resistance with the extension of treatment time (7,8). This E...

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“…Комбинация эндокринотерапии и блокаторов факторов роста может быть полезной стратегией для пре-одоления резистентности к эндокринотерапии [75] Определение Ki-67…”

Section: внутренние подтипыunclassified