Abstract 3950: Extracellular protons promote the metastasis of breast cancer via activation of the proton-sensing receptor G-protein coupled receptor 4

Acidosis of the tumor microenvironment is a typical malignant phenotype that enhances tumorigenesis and tumor progression induced by altered cellular signaling and transcriptional regulation. However, the underlying mechanism by which tumor cells sense and response the acidic environment remains unclear. In this study, we found that expression of G-protein coupled receptor (GPR4) was upregulated in breast cancer cells and tissues from patients with breast cancer compared to normal breast cells and tissues. In a xenograft mouse model, short hairpin RNA (shRNA)-mediated silencing of endogenous GPR4 significantly reduced distant metastases to several lymph nodes and the lung compared to control shRNA. In addition, endogenous GPR4 expression in breast cancer cells enhanced tumor cell migration and invasion in an acidic environment and induced the activation of RhoA and extracellular signal-regulated kinase (ERK) pathway. Acidosis/GPR4 activation also upregulated the expression of matrix metalloproteinase-9 (MMP9) and vascular endothelial growth factor (VEGF) in breast cancer cells. These findings highlight a novel mechanism by which acidosis-mediated tumor aggressiveness is acquired as a critical step for distant metastasis in breast cancer. Citation Format: Yu Jin Lee, Kyun Heo, Soo-Ah Park, Dong-Young Noh, Kyong-Tai Kim, Sung Ho Ryu, Pann-Ghill Suh Suh. Extracellular protons promote the metastasis of breast cancer via activation of the proton-sensing receptor G-protein coupled receptor 4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3950. doi:10.1158/1538-7445.AM2013-3950