E3 ubiquitin ligase HERC1 regulates breast cancer cells migration and invasion

ENRIQUÉ STEINBERG, JULIANA HAYDEÉ; ROSSI, MARIO; ROSSI, FABIANA A; JOSHI, MOLISHREE UMESH; CALVO ROITBERG, EZEQUIEL HERNÁN; ESPINOSA, JOAQUÍN MAXIMILIANO

Simposio; Buenos Aires Breast Cancer Symposium BA-BCS 2021; 2021

BABCS

Tumor cell migration and invasion into adjacent tissues is the first step towards secondary tumors formation. Tumoral dissemination is associated with a significant reduction in patients? survival and life quality, and it is considered an unmet clinical need. In order to identify novel regulators of tumor cell migration/invasion within components of this ubiquitination pathway, we performed a pooled genetic screen using an shRNA library against ubiquitination-related genes and a highly invasive breast cancer cell line. We set up a protocol to specifically enrich positive migration regulator candidates that involved in vitro and in vivo selection steps. Among the candidates we identified the E3 ligase HERC1. We demonstrated that its silencing reduces the migratory and invasive potential of breast cancer cells using in vitro experiments. We extended our investigation in vivo and confirmed that mice injected with HERC1 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci. Finally, we conducted an in-silico analysis and observed an inverse correlation between HERC1 expression levels and breast cancer patients? overall survival, suggesting that its overexpression could be a prognostic marker in patients with breast cancer. Altogether, our results highlight the potential of Herc1 as a novel putative therapeutic candidate for cancer treatment.