BRCA1 and acetyl-CoA carboxylase: the metabolic syndrome of breast cancer.
Breast cancer-associated mutations affecting the highly-conserved C-terminal BRCT domains of the tumor suppressor gene breast cancer susceptibility gene 1 (BRCA1) fully disrupt the ability of BRCA1 to interact with acetyl coenzyme A carboxylase alpha (ACCA), the rate-limiting enzyme catalyzing de novo fatty acid biogenesis. Specifically, BRCA1 interacts solely with the phosphorylated (inactive) form of ACCA (P-ACCA), and the formation of the BRCA1/P-ACCA complex interferes with ACCA activity by preventing P-ACCA dephosphorylation. One of the hallmarks of aggressive cancer cells is a high rate of energy-consuming anabolic processes driving the synthesis of lipids, proteins, and DNA (all of which are regulated by the energy status of the cell). The ability of BRCA1 to stabilize the phosphorylated/inactive form of ACCA strongly suggests that the tumor suppressive function of BRCA1 closely depends on its ability to mimic a cellular-low-energy status, which is known to block tumor cell anabolism and suppress the malignant phenotype. Interestingly, physical exercise and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA1 gene mutations. Further clinical work may explore a chemopreventative role of "low-energy-mimickers" deactivating the ACCA-driven "lipogenic phenotype" in women with inherited mutations in BRCA1. This goal might be obtained with current therapeutic approaches useful in treating the metabolic syndrome and associated disorders in humans (e.g., type 2 diabetes and obesity), including metformin, thiazolidinediones (TZDs), calorie deprivation, and exercise. Alternatively, new forthcoming ACCA inhibitors may be relevant in the management of BRCA1-dependent breast cancer susceptibility and development.
Brunet
Joan
J
Catalan Institute of Oncology (ICO)-Health Services Division of Catalonia, Catalonia, Spain.
Vazquez-Martin
Alejandro
A
Colomer
Ramon
R
Graña-Suarez
Begoña
B
Martin-Castillo
Begoña
B
Menendez
Javier A
JA
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000235:genetics*; D000263:Adenylate Kinase / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D006801:Humans; D050155:Lipogenesis; D024821:Metabolic Syndrome / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype
D004791:Enzyme Inhibitors; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase