The number of people with obesity is increasing rapidly worldwide. The German Cancer Research Center (DKFZ) recently reported that according to the WHO the number of children and adolescents with obesity increased tenfold between 1975 and 2016. Severe overweight can lead to various health impairments. Besides inducing cardiovascular diseases, obesity for example also promotes the development of cancer and metastases.
The current study elucidates an as yet unknown mechanism making breast cancer more aggressive. The enzyme ACC1* plays a central role in this process," said Dr. Mauricio Berriel Diaz, deputy director of the Institute for Diabetes and Cancer (IDC) at Helmholtz Zentrum München. He led the study together with Stephan Herzig, director of the IDC and professor for Molecular Metabolic Control at TUM and Heidelberg University Hospital. “ACC1 is a key component of fatty acid synthesis," said Berriel Diaz. “However, its function is impaired by the cytokines leptin and TGF-β.“ The levels of these cytokines are increased particularly in the blood of severely overweight subjects.
Fatty acid precursors promote metastases
The scientists demonstrated that the described inhibition of ACC1 leads to the accumulation of the fatty acid precursor acetyl-CoA. This precursor is transferred to certain gene “switches” that in turn increase the metastatic capacity of cancer cells by activating a specific gene program.
“Using human tissue from breast cancer metastases, we were able to show that ACC1 was significantly less active there," said Marcos Rios Garcia, first author of the study. When the scientists blocked the as yet unknown signaling pathway with an antibody (directed against the leptin receptor), this led to a significantly reduced metastatic spread of breast cancer tumors in an experimental model.
In the future, the researchers want to substantiate the data on the newly discovered mechanism in further studies. In addition, they are also considering related intervention points that could possibly be exploited therapeutically. “Blocking the signaling pathways and switching off the metastasis-related genes could be a therapeutic target," Herzig said. “As part of the so-called neoadjuvant therapy, the risk of metastases or the recurrence of tumors could be reduced prior to the surgical removal of the tumor.”
* ACC1 stands for acetyl-CoA-carboxylase 1, a central component of fatty acid synthesis. ACC1 mediates the chemical addition of carbon dioxide to acetyl-CoA, which results in malonyl-CoA. This reaction is the first and speed determining step in the fatty acid synthesis of all living organisms.
Metastasis of breast cancer or recurrence after surgical removal of the primary tumor is the main cause of cancer-related deaths in women. In addition, epidemiological studies show that obesity is associated with aggressive forms of breast cancer and that postmenopausal women in particular are at a higher risk of developing metastatic breast cancer.
The role of fatty acid synthesis for the altered energy metabolism of cancer cells is only incompletely understood. Various studies suggest that activation of fatty acid synthesis makes cancer cells independent from the supply with extracellular lipids. The present study reveals a new mechanism that is independent of fatty acid synthesis, in which the inactivation of ACC1 leads to the accumulation of acetyl-CoA, since it is no longer used for fatty acid synthesis but rather for the modification (acetylation) of regulatory proteins (transcription factors, e.g. SMAD2). The regulatory proteins modified in this way in turn switch on genes that contribute to increased aggressiveness of cancer cells.
Rios Garcia, M. et al. (2017): Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Recurrence. Cell Metabolism, DOI: 10.1016/j.cmet.2017.09.018