The angiogenic inducer CCN1 (
Cysteine-rich 61, CYR61) is differentially activated in metastatic
breast carcinomas. However, little is known about the precise mechanisms that underlie the pro-metastatic actions of CCN1. Here, we investigated the impact of CCN1 expression on
fatty acid synthase (FASN), a metabolic oncogene thought to provide
cancer cells with proliferative and survival advantages. Forced expression of CCN1 in MCF-7 cells robustly up-regulated FASN
protein expression and also significantly increased FASN gene promoter activity 2- to 3-fold, whereas deletion of the
sterol response element-
binding protein (SREBP) binding site in the FASN promoter completely abrogated CCN1-driven transcriptional activation. Pharmacological blockade of MAPK or PI-3'K activation similarly prevented the ability of CCN1 to induce FASN gene activation. Pharmacological inhibition of FASN activity with the
mycotoxin cerulenin or the small compound C75 reversed CCN1-induced acquisition of
estrogen independence and resistance to
hormone therapies such as
tamoxifen and
fulvestrant in anchorage-independent growth assays. This study uncovers FASNdependent endogenous lipogenesis as a new mechanism controlling the metastatic phenotype promoted by CCN1. Because
estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in
breast cancer, this previously unrecognized CCN1-driven lipogenic phenotype represents a novel metabolic target to clinically manage metastatic
disease progression.