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.
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.
INSERM, U1037, Toulouse, France; Institut Claudius Régaud, Toulouse France.
Marion
M
David
INSERM, U1033, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France; Faculté de Médecine Lyon Est, Lyon, France.
Debashish
D
Sahay
INSERM, U1033, Lyon, France; Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.
Florence
F
Mege
Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France.
Françoise
F
Descotes
INSERM, U1033, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France; Faculté de Médecine Lyon Est, Lyon, France.
Raphaël
R
Leblanc
INSERM, U1033, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France; Faculté de Médecine Lyon Est, Lyon, France.
Johnny
J
Ribeiro
INSERM, U1033, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France; Faculté de Médecine Lyon Est, Lyon, France.
Philippe
P
Clézardin
INSERM, U1033, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France; Faculté de Médecine Lyon Est, Lyon, France.
Olivier
O
Peyruchaud
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011422:Propionates / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D014408:Biomarkers, Tumor; D066257:Heparin-binding EGF-like Growth Factor; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid