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Lysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA 1–6 ). LPA receptor type 1 (LPA 1 ) signaling influences the pathophysiology of many diseases including cancer, obesity, rheumatoid arthritis, as well as lung, liver and kidney fibrosis. Therefore, LPA 1  is an attractive therapeutic target. However, most mammalian cells co-express multiple LPA receptors whose co-activation impairs the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. LPA 1  is known to induce IL-6 and IL-8 secretion, as also do LPA 2  and LPA 3 . In this work, we first determined the LPA induced early-gene expression profile in three unrelated human cancer cell lines expressing different patterns of LPA receptors (PC3: LPA 1,2,3,6 ; MDA-MB-231: LPA 1,2 ; MCF-7: LPA 2,6 ). Among the set of genes upregulated by LPA only in LPA 1 -expressing cells, we validated by QPCR and ELISA that upregulation of heparin-binding EGF-like growth factor (HB-EGF) was inhibited by LPA 1–3  antagonists (Ki16425, Debio0719). Upregulation and downregulation of HB-EGF mRNA was confirmed  in vitro  in human MDA-B02 breast cancer cells stably overexpressing LPA 1  (MDA-B02/LPA 1 ) and downregulated for LPA 1  (MDA-B02/shLPA 1 ), respectively. At a clinical level, we quantified the expression of LPA 1  and HB-EGF by QPCR in primary tumors of a cohort of 234 breast cancer patients and found a significantly higher expression of HB-EGF in breast tumors expressing high levels of LPA 1 . We also generated human xenograph prostate tumors in mice injected with PC3 cells and found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. All together our results demonstrate that HB-EGF is a new and relevant biomarker with potentially high value in quantifying LPA 1  activation state in patients receiving anti-LPA 1  therapies.

plos one

Identification of Heparin-Binding EGF-Like Growth Factor (HB-EGF) as a Biomarker for Lysophosphatidic Acid Receptor Type 1 (LPA1) Activation in Human Breast and Prostate Cancers