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

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。癌前病变细胞在致癌转化的过程中必须经历基本的代谢变化，因此确定导致这些变化的因素可能会揭示化学预防的新靶点和方法。肥胖、糖尿病和胰岛素抵抗，以及炎症细胞在乳腺脂肪组织中的浸润是乳腺癌的已知风险因素。酰基辅酶A二酰基甘油酰基转移酶（DGAT 1）通过用活化脂肪酸使二酰基甘油变性来催化甘油三酯的形成。在小鼠中靶向缺失DGAT 1基因的两个等位基因模拟在热量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。我们的数据表明，DGAT 1酶活性的抑制抑制乳腺癌细胞的生长，但不抑制正常细胞的增殖或活力。由于DGAT 1可以被小分子抑制剂靶向，因此DGAT 1抑制可能是一种有用的新型化学预防策略。我们假设DGAT 1的抑制限制了促进乳腺癌发生的关键因素，阻止了乳腺癌的发展， 表达SV40 T抗原的小鼠乳腺上皮中的乳腺癌。此外，我们假设这些变化依赖于乳腺组织本身缺乏DGAT 1活性。为了验证这一假设，我们提出了两个目标：（1）确定DGAT 1的缺乏或抑制是否减少了小鼠乳腺上皮中的增殖和炎症信号传导。(2)确定DGAT 1缺失对SV40 T抗原诱导的乳腺癌发展的影响。这些研究的结果将为开发有效和安全的方法来预防人类所有形式的乳腺癌提供临床前基础。

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.