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What makes breast cancer more aggressive?
Obesity appears to prompt the release of cytokines into our bloodstreams and kickstart breast cancer metastases by making cells more aggressive. Cytokine levels were greatly increased in the blood of severely overweight subjects. However, the team was also excited to find they could interrupt this conversion mechanism. Scientists from Helmholtz Zentrum München, Technische Universität München (TUM), Germany, and Heidelberg University Hospital reported their results in the journal Cell Metabolism.
"The enzyme ACC1 plays a central role in this process. ACC1 is a key component of fatty acid synthesis. However, its function was impaired by the cytokines leptin and TGF-ß."
The number of people with obesity is increasing rapidly worldwide. The German Cancer Research Center (DKFZ) recently reported that according to the World Health Organization or WHO, the number of obese children and adolescents increased tenfold between 1975 and 2016. Severe weight gain can lead to various health risks including cardiovascular diseases, but also promotes development of cancer and metastases.
The scientists demonstrated that inhibition of ACC1 leads to the accumulation of the fatty acid precursor acetyl-CoA. It is this precursor that is transferred to certain gene "switches," activating the specific gene program which increases the metastases of cancer cells.
Researchers want to continue exploring this newly discovered mechanism and examine the possibilities of developing new breast cancer therapies.>
According to Stephan Herzig PhD, director of the IDC and professor for Molecular Metabolic Control at TUM and Heidelberg University Hospital: "Blocking the signaling pathways and switching off the metastasis-related genes could be a therapeutic target. Part of neoadjuvant therapy to reduce risk of metastases or recurrence of tumors prior to surgical removal of a 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.
Background: 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.
• Leptin and TGF? inhibit ACC1 through TAK1-AMPK signaling in breast cancer
• Inhibition of ACC1 elevates acetyl-CoA, inducing Smad2 acetylation and EMT
• Blocking leptin-ACC1 axis counteracts metastasis formation in breast cancer
• Inactive pACC1 levels were increased in human breast cancer metastases
Breast tumor recurrence, and metastasis, represent the main causes of cancer-related death in women; and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) ? signaling. ACC1 phosphorylation was mediated by TGF?-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a “metabolocentric” approach in metastatic breast cancer therapy.
Authors: Marcos Rios Garcia, Brigitte Steinbauer, Kshitij Srivastava, Mahak Singhal, Frits Mattijssen, Adriano Maida, Sven Christian, Holger Hess-Stumpp, Hellmut G. Augustin, Karin Müller-Decker, Peter P. Nawroth, Stephan Herzig
Keywords: breast cancer, EMT, metastasis, pACC, acetyl-CoA, acetylation, leptin
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. helmholtz-muenchen. de/ en
The Institute for Diabetes and Cancer (IDC) is a member of the Helmholtz Diabetes Center (HDC) at the Helmholtz Zentrum München and a partner in the joint Heidelberg-IDC Translational Diabetes Program. The Institute for Diabetes and Cancer is tightly integrated into the German Center for Diabetes Research (DZD) and into the special research area "Reactive Metabolites and Diabetic Complications" at the Heidelberg University Medical School. The IDC conducts research on the molecular basis of severe metabolic disorders, including metabolic syndrome and type 2 diabetes, as well as their roles in tumor initiation and progression. http://www. helmholtz-muenchen. de/ idc
Technical University of Munich (TUM) is one of Europe's leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany. http://www. tum. de/ en/ homepage
Heidelberg University Hospital is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University belongs to the internationally most renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. With about 13,000 employees, training and qualification is an important issue. Every year, around 65,000 patients are treated on an inpatient basis, 56,000 cases on a day patient basis and more than 1,000,000 cases on an outpatient basis in more than 50 clinics and departments with almost 2,000 beds. Jointly with the German Cancer Research Center (DKFZ) and German Cancer Aid, Heidelberg University Hospital has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. Currently, about 3,700 future physicians are studying in Heidelberg; the reform Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany. http://www. klinikum. uni-heidelberg. de
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Breast cancer. Invasive cells appear light blue, stained for the leptin receptor, showing the ability of cells to metastasize. Cells of the nucleus are red. Image credit: Helmholtz Zentrum München