Targeting the lipid synthesis enzyme, DGAT1, for breast cancer prevention

针对脂质合成酶 DGAT1 预防乳腺癌

• 批准号: 8598686
• 负责人: Ivan Peter Uray
• 金额: $ 8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598686
• 关键词: 1,2-diacylglycerol; Acyl Coenzyme A; Adipose tissue; Alleles; Apoptotic; Aromatase; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Prevention; Breast Cancer Risk Factor; Caloric Restriction; Cell division; Cells; Chemoprevention; Chemopreventive Agent; DNA Fragmentation; Data; Dental crowns; Development; Diabetes Mellitus; Diet; Diglycerides; Dinoprostone; Disease; Elements; Energy Metabolism; Enzymes; Epithelium; Estrogen Receptors; Estrogens; Excision; Exhibits; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Foundations; Frequencies; Genes; Genotype; Glycerol; Goals; Growth; High Risk Woman; Human; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Insulin-Like Growth Factor I; Knockout Mice; Lipids; Longevity; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary gland; Measures; Metabolic; Metabolism; Mus; Normal Cell; Obesity; Oncogenes; Oncogenic; Pharmaceutical Preparations; Phenotype; Premalignant Cell; Prevention strategy; Preventive; Resistance; Risk; SV40 T Antigens; Signal Transduction; Simian virus 40; Structure; Testing; Time; Tissues; Transferase; Transplantation; Triglycerides; Wild Type Mouse; antigene; base; cancer cell; cancer prevention; carcinogenesis; diacylglycerol O-acyltransferase; enzyme activity; improved; in vivo; inhibitor/antagonist; insulin sensitivity; lipid biosynthesis; malignant breast neoplasm; mammary epithelium; novel; pre-clinical; prevent; public health relevance; small molecule; tumor

DESCRIPTION (provided by applicant): The use of anti-estrogenic agents in women at high risk for breast cancer has demonstrated that chemoprevention is achievable but all currently available options depend on the estrogen receptor. Premalignant cells must undergo fundamental metabolic changes on the path of oncogenic transformation, thus identifying the factors responsible for these changes may reveal new targets and approaches for chemoprevention. Obesity, diabetes and insulin resistance, as well as infiltration of inflammatory cells in the mammary fat tissue are known risk factors of breast cancer. The acyl-CoA diacylglcyerol acyl-transferase (DGAT1) enzyme catalyzes the formation of triglycerides by esterifying diacyl-glycerol with activated fatty acids. Targeted deletion of both alleles of the DGAT1 gene in mice mimics the phenotype observed under caloric restriction and increases insulin sensitivity, suppresses IGF levels, reduces fat stores and inflammation in the adipose tissues and increases life span. Our data show that inhibition of the DGAT1 enzyme activity suppresses the growth of breast cancer cells, but does not inhibit the proliferation or viability o normal cells. Because DGAT1 can be targeted by small molecule inhibitors DGAT1 inhibition may be a useful novel chemopreventive strategy. We hypothesize that suppression of DGAT1 limits the factors critical for the promotion of breast carcinogenesis, prevents the development of breast cancers in mouse mammary epithelium expressing the SV40 T antigen. Furthermore, we hypothesize that these changes are dependent upon the lack of DGAT1 activity in the mammary tissue itself. To test this hypothesis we propose two aims: (1) Determine whether the absence or inhibition of DGAT1 reduces proliferative and inflammatory signaling in breast epithelium in mice. (2) Determine the impact of the loss of DGAT1 on SV40 T antigen-induced breast cancer development. The results of these studies will provide the preclinical foundation to develop effective and safe ways to prevent all forms of breast cancer in humans.

描述(由申请人提供)：在乳腺癌高危女性中使用抗雌激素药物已经证明，化学预防是可以实现的，但目前所有可用的选择都取决于雌激素受体。癌前细胞在致癌转化过程中必须经历基本的代谢变化，因此识别导致这些变化的因素可能会揭示化学预防的新靶点和新方法。肥胖、糖尿病和胰岛素抵抗，以及乳房脂肪组织中炎症细胞的渗透，都是已知的乳腺癌风险因素。酰基辅酶A二酰甘油醇酰基转移酶(DGAT1)催化甘油二酯与活性脂肪酸的酯化反应生成甘油三酯。在小鼠中定向删除DGAT1基因的两个等位基因可以模拟卡路里限制下观察到的表型，并增加胰岛素敏感性，抑制IGF水平，减少脂肪组织中的脂肪储存和炎症，并延长寿命。我们的数据显示，抑制DGAT1酶的活性可以抑制乳腺癌细胞的生长，但不会抑制正常细胞的增殖或活力。因为DGAT1可以被小分子抑制剂靶向，所以抑制DGAT1可能是一种有用的新的化学预防策略。我们假设，抑制DGAT1限制了促进乳腺癌发生的关键因素，阻止了乳腺癌的发展 小鼠乳腺上皮中表达SV40T抗原的乳腺癌。此外，我们假设这些变化依赖于乳腺组织本身中DGAT1活性的缺乏。为了验证这一假设，我们提出了两个目标：(1)确定DGAT1的缺失或抑制是否会减少小鼠乳腺上皮细胞的增殖和炎症信号。(2)探讨DGAT1基因缺失对SV40T抗原诱导的乳腺癌发生的影响。这些研究的结果将为开发有效和安全的方法预防人类所有形式的乳腺癌提供临床前基础。