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Oncogenesis. 2014 Sep 1;3:e118. doi: 10.1038/oncsis.2014.32.

Membranous Nectin-4 expression is a risk factor for distant relapse of T1-T2, N0 luminal-A early breast cancer.

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1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] MediaPharma s.r.l., Chieti, Italy.
1] Department of Experimental and Clinical Sciences, Chieti, Italy [2] Center of Excellence for Research on Aging, Chieti, Italy [3] Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University, Chieti, Italy.
Department of Pathology, Regina Elena Cancer Institute, Rome, Italy.
CINBO Laboratories, University 'G. D'Annunzio', Chieti, Italy.


Nectins are Ca(2+)-independent immunoglobulin-like cell adhesion molecules that compose a family of four members that regulate several cellular activities such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses. Nectin-4 has recently emerged as a metastatis-associated protein in several cancers. Here, we have evaluated the association between the expression of Nectin-4 and the clinical outcome of patients with node-negative, T1/T2 breast cancers.The study group consisted of 197 patients presenting with primary unilateral breast carcinoma (T1/T2), with no evidence of nodal involvement and distant metastases. Nectin-4 protein expression was assessed by immunohistochemistry on tissue microarrays, and the results correlated with the clinical data using Kaplan-Meier curves and multivariate Cox regression analysis. Thirty-four out of 197 tumors (17.3%) exhibited Nectin-4 expression on cell membrane (m-Nectin-4) and 122 out of the 163m-Nectin-4 negative tumors (74.8%) showed high cytoplasmic expression of Nectin-4 (c-Nectin-4(High)). At Kaplan-Meier analysis, m-Nectin-4 positivity was significantly associated with a lower disease-free survival (DFS) and distant relapse-free survival (DRFS) rate in patients with a luminal-A phenotype (P=0.030 and P=0.002, respectively). Multivariate analysis showed that in luminal-A tumors m-Nectin-4 positivity is an independent prognostic factor for DFS (P=0.018) and DRFS (P=0.004), but not for local relapse-free survival (LRFS). On the other hand, c-Nectin-4(High) was significantly associated with higher rates of DFS and LRFS, but not DRFS, in the whole population (P=0.008 and P=0.004, respectively) and in patients with luminal-A tumors (P=0.022 and P=0.018, respectively). In patients with luminal-A tumors, multivariate analysis showed that the prognostic value of c-Nectin-4(Low/Negative) is limited to DFS (P=0.012) and LRFS (P=0.022). We suggest that Nectin-4 represents a prognostic factor and a therapeutic target in luminal-A early stage breast cancer.

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