E-cadherin inactivation by Trop-2 drives EMT-less metastatic relapse in triple-negative breast cancer

Tumor metastasis is the main cause of death for patients with triple-negative breast cancer (TNBC), and identification of metastasis drivers in TNBC is an urgent therapeutic need. Expression of target molecules in primary tumors and metastases was quantified using immunohistochemistry analysis. Cancer cell spheroids, wound healing, and cell aggregation assays were used to explore cell–cell adhesion. Pre-clinical models of metastatic diffusion and whole-transcriptome analysis were used to assess epithelial–mesenchymal transition (EMT) determinants and epithelial differentiation biomarkers. Patient survival and metastatic relapse were analyzed using Cox models and Kaplan-Meier plots. Trop-2 was similarly overexpressed across diverse experimental cancer metastasis models. Trop-2 binding to E-cadherin inactivated cell–cell adhesion through detachment of E-cadherin from the cytoskeleton. Release of β-catenin then led to anti-apoptotic signaling, increased cell migration, and enhanced cancer cell survival. We did not detect induction of EMT transcription factors or down-regulation of epithelial differentiation markers. This E-cadherin–inactivation pro-metastasis program was also seen in cancer patients (n=13,042 primary tumours). All TNBC patients with overexpression of Trop-2, E-cadherin inactivation and activation of β-catenin showed relapse within 8 years. No disease recurrence was observed in any of the control cases, devoid of activation of the Trop-2/E-cadherin/β-catenin module, over more than 12 years of follow-up. We have identified functional inactivation of E-cadherin by Trop-2 as a pivotal driver of EMT-less metastatic diffusion in TNBC. The sacituzumab govitecan-hziy anti–Trop-2 antibody has been shown to be effective in metastatic TNBC. Our findings provide support for a driving role and key therapeutic relevance of Trop-2 in TNBC.