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The alteration of cellular metabolic processes is a common event in the initiation and progression of several cancer types. One metabolic hallmark of cancer cells is an increase in de novo lipogenesis. The enzymes responsible for de novo fatty acid synthesis are overexpressed in cancer, suggesting that these enzymes may be appropriate targets in efforts to inhibit or treat disease. Specifically, Acetyl CoA Carboxylase 1 (ACC1), the cytosolic enzyme that catalyzes the rate limiting step of de novo fatty acid synthesis through the ATP and biotin-dependent carboxylation of acetyl-CoA to malonyl-CoA, has received attention as a potential target for cancer treatment. Pharmacological inhibition and siRNA mediated knockdown of ACC1 has been shown to selectively kill prostate cancer cells in vitro by denying cells of adequate amounts of fatty acids needed to proliferate and survive. Although ACC1 has been implicated in cancer, its role has not been examined in a spontaneous model of cancer. To address this issue, we first generated mice with prostate-specific deletion of exon 22 of the Acetyl CoA Carboxylase 1 (ACCL/L) gene by breeding with Probasin-Cre mice. Loss of ACC1 activity did not appear to affect prostate function as survival, prostate weight, histology, and breeding was similar between ACCL/L Cre+ and ACCL/L Cre− mice. To determine the role of ACC1 in prostate cancer, the ACC+/L mice were crossed with PtenL/L; Cre+ mice. To our surprise, ACC1 activity was not required for prostate cancer development or progression in vivo, despite its apparent requirement in vitro. Total prostate weight and individual lobe weight did not differ among ACC+/L; PtenL/L; Cre+ mice, ACCL/L; PtenL/L; Cre+ mice and ACC1+/+; PtenL/L; Cre+ mice. These early studies suggest that ACC1 activity, and perhaps the fatty acid synthesis pathway, may not be required for prostate cancer development. The role of ACC1 in redox modulation, rescue of impaired de novo fatty acid synthesis by circulating and dietary fatty acid, and the potential compensation for ACC1 activity by ACC2 in prostate cancer are possible explanations for this unexpected phenotype. These results could have significant impact on the development and use of anti-cancer therapeutics that target the fatty acid synthesis pathway. Citation Format: Amanda L. Davis, Kristen Scott, Yong Chen, Steven Kridel. Acetyl coA carboxylase1 and its role in prostate cancer initiation and progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1878. doi:10.1158/1538-7445.AM2013-1878