LACTB promotes breast cancer cell differentiation and suppresses breast tumorigenesis in vivo.
Major finding: LACTB promotes breast cancer cell differentiation and suppresses breast tumorigenesis in vivo.
Mechanism: LACTB reduces expression of the mitochondrial phospholipids LPE and PE to enhance differentiation.
Impact: LACTB may act as a tumor suppressor in breast cancer by altering mitochondrial lipid metabolism.
Cancers rarely arise in nonproliferative, terminally differentiated cell types such as adult myocytes and cardiomyocytes. This observation prompted Keckesova and colleagues to hypothesize that gene expression profiling of differentiated muscle cells could uncover tumor suppressor genes. Gene expression profiles revealed that LACTB, which encodes a mitochondrial protein, was overexpressed in differentiated, postmitotic muscle cells compared with muscle progenitor cells. LACTB has been suggested to promote intramitochondrial membrane organization, regulate electron transport chain complex I, and control cellular metabolism, but its cellular function is incompletely understood. Of 18 breast cancer cell lines, 15 exhibited reduced expression of LACTB compared to nontransformed cells, and 2 of the cell lines without reduced LACTB levels harbored a LACTB mutation. LACTB overexpression reduced proliferation in breast cancer cell lines and LACTB induction induced tumor regression in vivo, suggesting a tumor suppressive role for LACTB. Conversely, LACTB depletion was not sufficient to induce tumors in vivo, but concomitant expression of HRASG12V or MYCT58A resulted in tumor growth. LACTB expression promoted epithelial differentiation of breast cancer cells and reduced expression of the mitochondrial phospholipids lysophosphatidylethanolamines (LPE) and phosphatidylethanolamines (PE), which was mediated in part through a reduction in mitochondrial phosphatidylserine decarboxylase (PISD). Supplementing LACTB-expressing cancer cells with LPE increased proliferation and suppressed differentiation, suggesting that LACTB controls proliferation and differentiation via regulation of mitochondrial phospholipids. Together, these results elucidate a tumor suppressive role for LACTB and link mitochondrial lipid metabolism to cell differentiation in breast cancer.