Untangling the role of Transglutaminase type 2 in triple negative breast cancer progression

Breast Cancer is the most common malignancy and the second leading cause of cancer-related deaths among women. Despite the decrease in death rate due to prevention and new treatment strategies, drug resistance and recurrence still represent new challenges for researchers. Transglutaminase 2 (TG2) is a ubiquitously expressed protein with multiple intra and extracellular functions which have been associated to different diseases. However, in cancer its role is highly debated and controversial because of its tumour-specific oncogenic or tumour-suppressive effects. To highlight the role of TG2 in triple negative breast cancer (TNBC) progression, TG2 knock-out 4T1 cells were generated through CRISPR/Cas9 technology. Our data show that this enzyme depletion is associated with the reduction of neoplastic cell aggressiveness. To identify the underlying mechanisms, we characterized the in vitro tumorigenicity and metabolism of the TG2 knock-out clones. By biochemical analysis and bioenergetic studies, we demonstrate that TG2 absence impacts on breast cancer development and progression by affecting cell metabolism and in particular mitochondrial Complex I expression. All our data suggest TG2 as a therapeutic target to counteract drug-resistance in TNBC patients.