Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
Cancer Invasion and Metastasis Laboratory, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
Cell Death Dis. 2020 Feb 7;11(2):106. doi: 10.1038/s41419-020-2305-7.
Triple-negative breast cancer (TNBC) is a highly metastatic and deadly disease. TNBC tumors lack estrogen receptor (ERα), progesterone receptor (PR), and HER2 (ErbB2) and exhibit increased glutamine metabolism, a requirement for tumor growth. The G protein-coupled kisspeptin receptor (KISS1R) is highly expressed in patient TNBC tumors and promotes malignant transformation of breast epithelial cells. This study found that TNBC patients displayed elevated plasma kisspeptin levels compared with healthy subjects. It also provides the first evidence that in addition to promoting tumor growth and metastasis in vivo, KISS1R-induced glutamine dependence of tumors. In addition, tracer-based metabolomics analyses revealed that KISS1R promoted glutaminolysis and nucleotide biosynthesis by increasing c-Myc and glutaminase levels, key regulators of glutamine metabolism. Overall, this study establishes KISS1R as a novel regulator of TNBC metabolism and metastasis, suggesting that targeting KISS1R could have therapeutic potential in the treatment of TNBC.
三阴性乳腺癌（TNBC）是一种高度转移性和致命性的疾病。TNBC 肿瘤缺乏雌激素受体（ERα）、孕激素受体（PR）和 HER2（ErbB2），并表现出增加的谷氨酰胺代谢，这是肿瘤生长的必需条件。G 蛋白偶联的 kisspeptin 受体（KISS1R）在患者的 TNBC 肿瘤中高度表达，并促进乳腺上皮细胞的恶性转化。本研究发现，与健康受试者相比，TNBC 患者的血浆 kisspeptin 水平升高。这也首次提供了证据，表明除了在体内促进肿瘤生长和转移外，KISS1R 还通过增加 c-Myc 和谷氨酰胺酶的水平来诱导肿瘤对谷氨酰胺的依赖性，这些是谷氨酰胺代谢的关键调节剂。总的来说，这项研究确立了 KISS1R 是 TNBC 代谢和转移的新调节剂，表明靶向 KISS1R 可能具有治疗 TNBC 的潜在治疗作用。
