G protein-coupled kisspeptin receptor induces metabolic reprograming and tumorigenesis in estrogen receptor-negative breast cancer

• Published in: Cell death & disease Vol. 11; no. 2; p. 106
• Main Authors: Dragan, Magdalena, Nguyen, Mai-Uyen, Guzman, Stephania, Goertzen, Cameron, Brackstone, Muriel, Dhillo, Waljit S., Bech, Paul R., Clarke, Sophie, Abbara, Ali, Tuck, Alan B., Hess, David A., Pine, Sharon R., Zong, Wei-Xing, Wondisford, Frederic E., Su, Xiaoyang, Babwah, Andy V., Bhattacharya, Moshmi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.02.2020; Springer Nature B.V
• Subjects: 13; 13/106; 13/109; 13/51; 13/89; 13/95; 631/67/1347; 631/67/2327; 631/67/322; 64/60; 82/80; Adult; Aged; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Breast cancer; c-Myc protein; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Case-Control Studies; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cellular Reprogramming; Energy Metabolism; Epithelial cells; ErbB-2 protein; Female; Gene Expression Regulation, Neoplastic; Glutaminase; Glutaminase - genetics; Glutaminase - metabolism; Glutamine; Glutamine - metabolism; Humans; Immunology; Kiss1 protein; Life Sciences; Metabolism; Metabolomics; Metastases; Metastasis; Mice, Inbred NOD; Mice, SCID; Middle Aged; Myc protein; Neoplasm Invasiveness; Nucleotides - metabolism; Progesterone; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Kisspeptin-1 - genetics; Receptors, Kisspeptin-1 - metabolism; Signal Transduction; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Tumor Burden; Tumorigenesis; Tumors; Young Adult
• ISSN: 2041-4889; 2041-4889
• 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.