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.
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Zuzana
Z
Keckesova
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Joana Liu
JL
Donaher
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Jasmine
J
De Cock
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.|Metabolon, Inc., PO Box 110407, Research Triangle Park, North Carolina 27709, USA.
Elizaveta
E
Freinkman
Department of Medicine and the Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Susanne
S
Lingrell
Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.|Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Daniel A
DA
Bachovchin
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Brian
B
Bierie
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
Verena
V
Tischler
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
Aurelia
A
Noske
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Marian C
MC
Okondo
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Ferenc
F
Reinhardt
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Prathapan
P
Thiru
Broad Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Todd R
TR
Golub
Department of Medicine and the Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Jean E
JE
Vance
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|MIT Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Robert A
RA
Weinberg
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002262:Carboxy-Lyases / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010714:Phosphatidylethanolamines; D025521:Tumor Suppressor Proteins; C483858:phosphatidylethanolamine; C486706:LACTB protein, human; D001618:beta-Lactamases; D002262:Carboxy-Lyases; C022353:phosphatidylserine decarboxylase