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Estrogen Receptor Α Promotes Breast Cancer by Reprogramming Choline Metabolism

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Estrogen Receptor Α Promotes Breast Cancer by Reprogramming Choline Metabolism Published OnlineFirst July 25, 2016; DOI: 10.1158/0008-5472.CAN-15-2910 Cancer Integrated Systems and Technologies Research Estrogen Receptor a Promotes Breast Cancer by Reprogramming Choline Metabolism Min Jia1, Trygve Andreassen2, Lasse Jensen3,4, Tone Frost Bathen5, Indranil Sinha1, Hui Gao1, Chunyan Zhao1, Lars-Arne Haldosen1, Yihai Cao3, Leonard Girnita6, Siver Andreas Moestue5, and Karin Dahlman-Wright1 Abstract Estrogen receptor a (ERa) is a key regulator of breast growth and identified as a direct ERa-regulated gene, was required for estro- breast cancer development. Here, we report how ERa impacts gen-induced effects on Cho metabolism, including increased these processes by reprogramming metabolism in malignant phosphatidylcholine synthesis. CHPT1 silencing inhibited anchor- breast cells. We employed an integrated approach, combining age-independent growth and cell proliferation, also suppressing genome-wide mapping of chromatin-bound ERa with estrogen- early-stage metastasis of tamoxifen-resistant breast cancer cells induced transcript and metabolic profiling, to demonstrate that in a zebrafish xenograft model. Our results showed that ERa pro- ERa reprograms metabolism upon estrogen stimulation, including motes metabolic alterations in breast cancer cells mediated by changes in aerobic glycolysis, nucleotide and amino acid synthesis, its target CHPT1, which this study implicates as a candidate thera- and choline (Cho) metabolism. Cho phosphotransferase CHPT1, peutic target. Cancer Res; 76(19); 1–13. Ó2016 AACR. Introduction lated to hormone receptor status, including differences in gluta- mine and b-alanine metabolism, as well as phospholipid metab- Complementary to viewing cancer as a genetic disease, cancer olism (9–11). Furthermore, estrogen stimulation enhanced the can be considered a metabolic disease (1, 2). Altered metabolism rate of glucose consumption, lactate production (aerobic glycol- in cancer directs enhanced nutrient acquisition and facilitates ysis), and glutamate synthesis and decreased the level of phos- assimilation of carbon into macromolecules, such as lipids, phocholine (PCho) in breast cancer cell lines (12–14). proteins, and nucleic acids. The net effect of these activities is to Choline (Cho) is an essential nutrient that is necessary for cell support cell growth and proliferation (3–6). membrane synthesis and functions as an important methyl 17b-Estradiol (E2) and its receptor estrogen receptor a (ERa) donor (15, 16). Routing of Cho through its various metabolic have been implicated in promoting proliferation, survival, and pathways is cell and tissue specific (17). Following uptake of migration of breast cancer cells through multiple mechanisms, Cho, the intracellular metabolism of Cho is partitioned along thereby contributing to tumor growth and progression (7, 8). þ two major pathways: (i) converted to PCho for the synthesis of Individuals with ERa-positive (ERa ) breast cancer as determined phosphatidylcholine (PtdCho), a major constituent of cell mem- by IHC account for approximately 70% of breast cancer patients. þ branes; or (ii) oxidation to produce the methyl donor betaine Comparative metabolomics profiling of ERa and ERa-negative À (16). Abnormally high synthesis of PtdCho via the cytidine (ERa ) breast cancer indicated clear metabolic differences corre- diphosphate–choline (CDP-Cho) pathway, where CTP:phos- phocholine cytidylyltransferase (CCT) has been identified as the rate-limiting enzyme, is generally recognized as a metabolic 1Department of Biosciences and Nutrition, Novum, Karolinska Institu- hallmark of cancer (18, 19). PtdCho can also be synthesized 2 tet, Huddinge, Sweden. Department of Circulation and Medical Imag- through methylation of phosphatidylethanolamine (PE) by ing, MR Core Facility, Norwegian University of Science and Technol- ogy, Trondheim, Norway. 3Department of Microbiology, Tumor, and phosphatidylethanolamine N-methyltransferase (PEMT; ref. 20). Cell Biology, Karolinska Institutet, Stockholm, Sweden. 4Department The PEMT gene has been shown to be induced by estrogen in of Medical and Health Sciences, Unit of Cardiovascular Medicine, hepatocytes (20). Linkoping€ University, Linkoping,€ Sweden. 5Department of Circulation and Medical Imaging, Norwegian University of Science and Technol- Increased levels of PCho and total Cho-containing metabo- ogy, Trondheim, Norway. 6Department of Oncology and Pathology, lites have been identified as markers for breast cancer (21). Karolinska Institutet and Karolinska University Hospital, Stockholm, Furthermore, increased synthesis of PtdCho is one of the earliest Sweden. metabolic events associated with the initial stimulation of cell Note: Supplementary data for this article are available at Cancer Research growth and proliferation by tumor promoters in normal cells Online (http://cancerres.aacrjournals.org/). (22–24). PtdCho has also been found to be increased in breast Corresponding Authors: Min Jia, Department of Biosciences and Nutrition, cancer cells by tumor promoter (25). Consistently, human Karolinska Institute, Halsov€ agen€ 7-9, Stockholm 14183, Sweden. Phone: 468- breast cancer cells have been shown to have higher levels of 5248-1221; Fax: 468-5248-1130; E-mail: [email protected]; and Karin Dahlman- PtdCho than normal human mammary epithelial cells (26). Wright, [email protected] Underlying mechanisms and potential drug targets in abnormal doi: 10.1158/0008-5472.CAN-15-2910 Cho phospholipid metabolism have been widely investigated in Ó2016 American Association for Cancer Research. different cancers, as reviewed in ref. 19. Overall, the regulation www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst July 25, 2016; DOI: 10.1158/0008-5472.CAN-15-2910 Jia et al. of Cho phospholipid metabolism in breast cancer cells has been inant analysis on Pareto-scaled NMR spectra using PLS_Tool- shown to depend on breast cancer subtype with respect to gene box v7.5.2 (Eigenvector Research Inc.). This technique identi- expression profiles and metabolic fingerprints (27). fies linear combinations of metabolic features referred to as Several studies have provided important insights into global latent variables (LV) that discriminate between classes of sam- estrogen-regulated gene networks based on profiling ERa-bind- ples. Quantification was performed by binning spectral regions ing regions and estrogen-regulated expression (28–33). To containing signals from identified metabolites. To aid in the extend global estrogen-regulated networks to effects on breast identification of these metabolites, Chenomx NMR suite v7.7 cancer metabolism, we report a comprehensive analysis of (Chenomx Inc.) was used. In addition, various 2D NMR spectra estrogen-regulated metabolic pathways in two breast cancer (HSQC, HMBC, COSY, TOCSY) were recorded to assure cell lines. We integrate cistrome, transcriptome, and metabo- identification. lome data to identify metabolic pathways regulated by estrogen signaling via ERa. We focus on effects conserved between two Tissue microarray analysis þ ERa breast cancer cell lines with the aim to identify general CHPT1 expression in human breast cancers was analyzed in effectors of metabolic signaling rather than cell type-specific tissue microarrays (TMA; US BioMax BR1503d) by IHC. Anti- effects. CHPT1 antibody was from The Human Protein Atlas. fi Materials and Methods Zebra sh metastatic model Tamoxifen-sensitive MCF7 cells and tamoxifen-resistant LCC2 Additional and detailed methods are included in the Supple- cells were used. The zebrafish metastatic model was established as mentary Materials and Methods. described previously (35). Cell culture MCF7 cells developed at the Michigan Cancer Foundation Results þ (Detroit, MI) were kindly provided by Dr. Robert P.C. Shiu A core set of direct ERa-regulated genes in ERa breast (University of Manitoba, Winnipeg, Manitoba, Canada; 2012). cancer cells T47D cells were purchased from the ATCC (2004). Tamoxifen- To identify a core set of direct ERa-regulated genes, we sensitive MCF7 cells and tamoxifen-resistant LCC2 cells were combined genomewide ERa-binding profiles with detailed tran- kindly provided by Dr. Janne Lehtio€ (Karolinska Institutet, Stock- script profiling for the two breast cancer cell lines, MCF7 and holm, Sweden; 2012). LCC2 cells originate from MCF-7 cells. T47D. A total of 18,040 and 12,659 ERa-binding regions were These cell lines were authenticated by short tandem repeat pro- identified for MCF7 cells and T47D cells, respectively (Fig. 1A). filing (Uppsala Genome Center, Uppsala, Sweden) in June 2016. General properties of the identified ERa-binding regions, such MCF7 and LCC2 cells were maintained in DMEM supplemented as peak distribution and enriched motifs, are consistent with with 10% FBS and 1% penicillin/streptomycin (Gibco). T47D previously published studies (Supplementary Fig. S1A–S1C). cells were grown in RPMI1640 supplemented with 10% FBS and Overlaying the MCF7 and T47D cistromes revealed 6,480 shared 1% penicillin/streptomycin. DMEM and RPMI1640 culture medi- binding regions, corresponding to 36% and 51% of the MCF7 um contain 28.57 and 21.43 mmol/L Cho, respectively. The and T47D cistromes, respectively (Fig. 1A and B). The shared content of Cho and Cho phospholipid in bovine serum is not binding regions overlapped with published ERa cistromes for provided by the manufacturer. No additional growth factors were breast cancer cell lines (Supplementary
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