Abstract PD15-04: Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse

Hundreds of proteins/genes have been linked to the metastatic phenotype. However, consistent markers of tumour aggressiveness and metastatic potential in breast cancer patients were not identified, not even including proteomic analysis and large-scale genome sequencing.Metastasis-associated genes were predicted to include not only drivers of the metastatic phenotype, but also secondary events, together with adaptive, counterbalancing changes. Thus, to identify candidates with a required role in metastatic diffusion, we looked for genes that were concordantly dysregulated across orthogonal cancer metastasis settings. This led us to identify Trop-2 as uniquely upregulated and associated to metastasis in experimental models of breast cancer, as well as in other solid tumors. We identified functional inactivation of E-cadherin by Trop-2 as the main motor of metastatic diffusion of such metastatic systems. Trop-2 binding to E-cadherin inactivated its cell-cell adhesion function, through release from the cytoskeleton, for activation of β-catenin transcriptional activity. This led to anti-apoptotic signaling, increased cell migration capacity and enhanced cancer cell survival. We showed that this mechanism led to metastatic diffusion of xenotransplants growing in immunosuppressed mice. An E-cadherin-inactivation metastasis program was then shown to be recapitulated in breast cancer patients, as well as in other solid tumors, over 24 independent case series, encompassing 13,042 primary tumours. Aggressive triple-negative breast cancers were shown to be driven toward global relapse by Trop-2 overexpression, through E-cadherin inactivation and activation of β-catenin transcriptional activity. No disease recurrence was observed in control cases over +12 years of follow-up. These finding lead to a novel paradigm of a Trop-2-driven, E-cadherin-inactivation program as a main metastasis driver in solid tumors. This may open far-reaching perspectives in diagnostic procedures and anti-cancer therapies. Citation Format: Saverio Alberti, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, Patrizia Querzoli, Massimo Pedriali, Laura Antolini, Emanuela Guerra. Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-04.