Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.
Department of Circulation and Medical Imaging, MR Core Facility, Norwegian University of Science and Technology, Trondheim, Norway.
Cancer Res. 2016 Oct 1;76(19):5634-5646. doi: 10.1158/0008-5472.CAN-15-2910. Epub 2016 Jul 25.
Estrogen receptor α (ERα) is a key regulator of breast growth and breast cancer development. Here, we report how ERα impacts these processes by reprogramming metabolism in malignant breast cells. We employed an integrated approach, combining genome-wide mapping of chromatin-bound ERα with estrogen-induced transcript and metabolic profiling, to demonstrate that ERα reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline (Cho) metabolism. Cho phosphotransferase CHPT1, identified as a direct ERα-regulated gene, was required for estrogen-induced effects on Cho metabolism, including increased phosphatidylcholine synthesis. CHPT1 silencing inhibited anchorage-independent growth and cell proliferation, also suppressing early-stage metastasis of tamoxifen-resistant breast cancer cells in a zebrafish xenograft model. Our results showed that ERα promotes metabolic alterations in breast cancer cells mediated by its target CHPT1, which this study implicates as a candidate therapeutic target. Cancer Res; 76(19); 5634-46. ©2016 AACR.
雌激素受体 α（ERα）是乳腺生长和乳腺癌发展的关键调节因子。在这里，我们报告 ERα 如何通过重新编程恶性乳腺细胞中的代谢来影响这些过程。我们采用了一种综合方法，将染色质结合的 ERα 的全基因组作图与雌激素诱导的转录和代谢谱相结合，证明 ERα 在雌激素刺激下重新编程代谢，包括有氧糖酵解、核苷酸和氨基酸合成以及胆碱（Cho）代谢的变化。Cho 磷酸转移酶 CHPT1 被确定为直接受 ERα 调控的基因，它是雌激素诱导的 Cho 代谢变化所必需的，包括增加磷酸胆碱的合成。CHPT1 沉默抑制了锚定非依赖性生长和细胞增殖，也抑制了他莫昔芬耐药乳腺癌细胞在斑马鱼异种移植模型中的早期转移。我们的研究结果表明，ERα 通过其靶基因 CHPT1 促进乳腺癌细胞中的代谢改变，该研究将 CHPT1 作为候选治疗靶点。Cancer Res; 76(19); 5634-46. ©2016 AACR.
