Home LiteratureArticle Details

PMID: 24828490 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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.

PloS one ·Vol. 9 ·No. 5 ·2014-00-00 ·Pages e97771

David M, Sahay D, Mege F, Descotes F, Leblanc R, Ribeiro J, Clézardin P, Peyruchaud O

Abstract

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 (LPA₁₋₆). LPA receptor type 1 (LPA₁) signaling influences the pathophysiology of many diseases including cancer, obesity, rheumatoid arthritis, as well as lung, liver and kidney fibrosis. Therefore, LPA₁ 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. LPA₁ is known to induce IL-6 and IL-8 secretion, as also do LPA₂ and LPA₃. 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: LPA₁,₂,₆; MDA-MB-231: LPA1,2; MCF-7: LPA₂,₆). Among the set of genes upregulated by LPA only in LPA₁-expressing cells, we validated by QPCR and ELISA that upregulation of heparin-binding EGF-like growth factor (HB-EGF) was inhibited by LPA₁-₃ antagonists (Ki16425, Debio0719). Upregulation and downregulation of HB-EGF mRNA was confirmed in vitro in human MDA-B02 breast cancer cells stably overexpressing LPA₁ (MDA-B02/LPA₁) and downregulated for LPA₁ (MDA-B02/shLPA1), respectively. At a clinical level, we quantified the expression of LPA₁ 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 LPA₁. 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 LPA₁ activation state in patients receiving anti-LPA₁ therapies.

MeSH Terms

Animals Biomarkers, Tumor/genetics,metabolism Breast Neoplasms/drug therapy,genetics,metabolism,pathology Cell Line, Tumor Female Gene Expression Regulation, Neoplastic Heparin-binding EGF-like Growth Factor/genetics,metabolism Humans Isoxazoles/pharmacology Lysophospholipids/pharmacology Male Mice Mice, Inbred BALB C Mice, Nude Propionates/pharmacology Prostatic Neoplasms/drug therapy,genetics,metabolism,pathology RNA, Messenger/antagonists & inhibitors,genetics,metabolism Receptors, Lysophosphatidic Acid/antagonists & inhibitors,genetics,metabolism Signal Transduction Xenograft Model Antitumor Assays

Chemicals

3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid Biomarkers, Tumor Heparin-binding EGF-like Growth Factor Isoxazoles Lysophospholipids Propionates RNA, Messenger Receptors, Lysophosphatidic Acid lysophosphatidic acid

Authors & Affiliations

8 authors, click to expand affiliations / ORCID

David Marion

INSERM, U1037, Toulouse, France; Institut Claudius Régaud, Toulouse France.

Sahay Debashish