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.
The goal of this study is to test the removal of the lipid synthesis enzyme DGAT1 as a basis for a novel cancer preventive strategy. While DGAT1 serves no essential functions in normal metabolism, two disease conditions that represent important risk factors for breast cancer, obesity and diabetes, were shown to improve by the deletion or inhibition of DGAT1. Thus we propose to determine whether deletion of DGAT1 function could suppress the formation of breast cancers triggered by a known tumor-inducing gene, and whether systemic or local removal of DGAT1 is necessary for the cancer inhibitory effect. Because DGAT1 can be targeted by small drug-like molecules, DGAT1 inhibition may become a promising novel chemopreventive strategy.
|Uray, Iván P; Dmitrovsky, Ethan; Brown, Powel H (2016) Retinoids and rexinoids in cancer prevention: from laboratory to clinic. Semin Oncol 43:49-64|