LACTB is a tumour suppressor that modulates lipid metabolism and cell state

Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression. LACTB modulates mitochondrial lipid metabolism and changes the differentiation state of breast cancer cells, thereby negatively affecting the growth of various tumorigenic, but not non-tumorigenic, cells both in vitro and in vivo. Cancer can arise in almost every type of cell, but some tissue types, such as the heart, skeletal muscle and the brain, seem remarkably resistant. The cells in these tissues, such as myocytes in muscles, are typically non-proliferative, highly specialized, and generate energy by oxidative phosphorylation, rather than glycolysis — all characteristics that are in stark contrast to cancer cells. Robert Weinberg and colleagues therefore investigated whether such cells contain some form of tumour suppressor. From in vitro and in vivo studies in mice and humans, the authors identify LACTB as a novel mitochondrial tumour suppressor. In breast cancer, LACTB prevents the transformation to a tumour through linked roles in mitochondrial lipid metabolism and the promotion of cellular differentiation.