De novo lipogenesis is the metabolic pathway by which cells produce fatty acids that are critical for a range of cellular processes such as membrane synthesis, cell signalling and energy storage. Acetyl-CoA carboxylase (ACC) is a key regulator of lipid biosynthesis and while increased lipid metabolism is a feature of aggressive cancers, very little is known about the role of ACC1 or increased lipid metabolism in breast cancer.
This study employed ACC1 mammary specific knockout mice, ACC1 & ACC2 sh- and siRNA interference and ACC pharmacological inhibitors to examine the role of ACC1 in mammary gland development and breast cancer progression. Immunohistochemical analysis demonstrated that ACC1 is not normal expressed by breast epithelium but its expression is upregulated during lactation and breast carcinogenesis. Mammary specific deletion of ACC1 did not overly perturb normal mammary gland development, but resulted in reduced pup growth rates and decreased milk fat production during lactation.
In contrast to its role in mammopoiesis, targeting ACC1 in preclinical mouse models of breast cancer resulted in reduced tumour growth, enhanced overall survival and decreased number of metastatic lesions. Furthermore, both genetic and pharmacological inhibitors of ACC1 inhibited human breast cancer cell growth and survival, and enhanced the effects of some of our current breast cancer therapeutics such as Tamoxifen.
Taken together these data indicate an exciting new role for ACC1 as a novel therapeutic target and key regulator of human breast cancer.