Nectin-4 is a new histological and serological tumor associated marker for breast cancer

Abstract

IntroductionBreast cancer is a complex and heterogeneous disease at the molecular level. Evolution is difficult to predict according to classical histoclinical prognostic factors. Different studies highlight the importance of large-scale molecular expression analyses to improve taxonomy of breast cancer and prognostic classification. Identification of new molecular markers that refine this taxonomy and improve patient management is a priority in the field of breast cancer research.Nectins are cell adhesion molecules involved in the regulation of epithelial physiology. We present here Nectin-4/PVRL4 as a new histological and serological tumor associated marker for breast carcinoma.MethodsExpression of Nectin-4 protein was measured on a panel of 78 primary cells and cell lines from different origins and 57 breast tumors by FACS analysis and immunohistochemistry (IHC), respectively. mRNA expression was measured by quantitative PCR.Serum Nectin-4 was detected by ELISA and compared with CEA and CA15.3 markers, on panels of 45 sera from healthy donors, 53 sera from patients with non-metastatic breast carcinoma (MBC) at diagnosis, and 182 sera from patients with MBC. Distribution of histological/serological molecular markers and histoclinical parameters were compared using the standard Chi-2 test.ResultsNectin-4 was not detected in normal breast epithelium. By contrast, Nectin-4 was expressed in 61% of ductal breast carcinoma vs 6% in lobular type. Expression of Nectin-4 strongly correlated with the basal-like markers EGFR, P53, and P-cadherin, and negatively correlated with the luminal-like markers ER, PR and GATA3. All but one ER/PR-negative tumors expressed Nectin-4. The detection of Nectin-4 in serum improves the follow-up of patients with MBC: the association CEA/CA15.3/Nectin-4 allowed to monitor 74% of these patients compared to 67% with the association CEA/CA15.3. Serum Nectin-4 is a marker of disease progression, and levels correlate with the number of metastases (P = 0.038). Serum Nectin-4 is also a marker of therapeutic efficiency and correlates, in 90% of cases, with clinical evolution.ConclusionNectin-4 is a new tumor-associated antigen for breast carcinoma. Nectin-4 is a new bio-marker whose use could help refine breast cancer taxonomy and improve patients' follow-up. Nectin-4 emerges as a potential target for breast cancer immunotherapy.

Enfortumab Vedotin Antibody–Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models

“…Generally, we observed similar overall frequency of nectin-4 expression in ovarian cancer as previously published by Derycke and colleagues (26). Soluble form of Nectin-4 in patient serum and in ascites in case of ovarian cancer has been reported (24)(25)(26). Although the levels varied between reports, all investigators show an association between higher detected levels of soluble nectin-4 and disease progression.…”

“…More recently, nectin-4 was identified as an entry point for measles and other viruses and was proposed as a target for oncolytic viral therapy (21,22). Although several groups reported the detection of nectin-4 expression in breast, ovarian, and lung cancers (23)(24)(25)(26), no comprehensive analysis has been reported to date. Using suppression subtractive hybridization, we identified nectin-4 as one of the genes dramatically upregulated in bladder cancer specimens.…”

Nectines et nectines-like

“…Cependant, par rapport aux autres membres de la famille, nectine-4 présente un profil d'expression unique car normalement restreint au stade embryonnaire [4]. La protéine est réexpri-mée dans des tumeurs mammaires de mauvais pronostic alors qu'elle est absente du tissu épithélial mammaire sain [30]. Une forme soluble, correspondant à la région extracellulaire de nectine-4, est générée par clivage protéolytique impliquant la métalloprotéase ADAM17 (A disintegrin and metalloproteinase domain 17 encore appelée TACE pour tumor necrosis factor--converting enzyme) [31,41].…”

Expression of nectin-4 as a potential biomarker in enzootic nasal adenocarcinoma of goats

“…The nectin family belongs to the Ca 2+ -independent immunoglobulin-like molecules and is comprised of four members named nectin-1, -2, -3, and -4. This family plays a role in cell-cell adhesion that regulates the formation of adherent junctions and tight junctions by epithelial cells in a homophilic and a heterophilic manner (Fabre-Lafay et al, 2007;Takai et al, 2008). The cytoplasmic region of nectins binds afadin, which directly connects to the actin cytoskeleton (Takai et al, 2003).…”

“…The cytoplasmic region of nectins binds afadin, which directly connects to the actin cytoskeleton (Takai et al, 2003). Nectin-4 is a type I transmembrane glycoprotein which has recently proven to be overexpressed in human breast carcinoma and is thus considered a specific tumour-associated marker, as the normal mammary gland lacks nectin-4 expression (Fabre-Lafay et al, 2007). In non-small cell lung cancer, a high level of nectin-4 expression has been shown to be associated with a poor prognosis (Takano et al, 2009).…”