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

Authors

Magdalena Dragan, Rutgers Robert Wood Johnson Medical School at New Brunswick
Mai Uyen Nguyen, Rutgers Robert Wood Johnson Medical School at New Brunswick
Stephania Guzman, Rutgers Robert Wood Johnson Medical School at New Brunswick
Cameron Goertzen, University of Toronto
Muriel Brackstone, London Health Sciences Centre
Waljit S. Dhillo, Imperial College London
Paul R. Bech, Imperial College London
Sophie Clarke, Imperial College London

Document Type

Article

Publication Date

2-1-2020

Journal

Cell Death and Disease

Volume

11

Issue

2

URL with Digital Object Identifier

10.1038/s41419-020-2305-7

Abstract

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.