Acetyl-CoA carboxylase 1-dependent lipogenesis drives breast cancer progression

Abstract

Dysregulation of cellular energetics, including lipid synthesis mediated through de novo lipogenesis, is a feature of many cancers. Here we report that acetyl-coenzyme A carboxylase (ACC) 1, the rate-limiting enzyme of de novo lipogenesis, is a key regulator of breast cancer progression and cancer cell phenotype. Mammary epithelial-specific deletion of ACC1 impaired tumour progression and decreased cancer cell proliferation in the PyMT model of breast cancer in vivo. ACC1 knockout in human breast cancer cell lines resulted in decreased cell number and altered cell and membrane morphology. Lipidomic profiling demonstrated reduced levels of acyl-carnitines (CARs) and several phospholipid (PL) classes, whilst also shifting the lipid profiles to exhibit more elongated and less saturated lipids in ACC1 knockout breast cancer cells. Palmitate rescue of ACC1 deletion phenotypes demonstrated a critical role for ACC1 driven de novo lipogenesis in breast cancer cell function. Analysis of human breast tumour-microarrays identified strong ACC1 expression at all breast cancer stages, grade and metastasis, compared to normal adjacent tissue. Together our data demonstrate a novel role for ACC1 in breast cancer progression and cancer cell function, mediated through its lipogenic role, that together with its expression profile, identify ACC1 as a potential therapeutic target in breast cancer.