Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression.

Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor , , and expression correlated with a less aggressive phenotype, while high expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low , , and expression and high expression. LPAR levels were lower in tumors over normal breast tissue for , , , and , while the opposite was observed for and . and were highest in cancer-associated fibroblasts, while was highest in endothelial cells, and was highest in cancer epithelial cells. Tumors high in and had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.