title: The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells.
abstract: 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 increasedFASNgene promoter activity 2- to 3-fold, whereas deletion of the sterol response element-binding protein (SREBP) binding site in theFASNpromoter completely abrogated CCN1-driven transcriptional activation. Pharmacological blockade of MAPK or PI-3'K activation similarly prevented the ability of CCN1 to induceFASNgene 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.
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain; Girona Biomedical Research Institute (IDIBGI), Girona, Spain.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.affiliation: IBYME, CONICET-Laboratorio de Immunohematología, Buenos Aires, Argentina.
authors.forename: Luciano
authors.initials: L
authors.lastname: Vellon
authors.affiliation: Cancer Institute, University of Mississippi, Jackson, MS, USA; Department of Preventive Medicine, University of Mississippi, Jackson, MS, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Espinoza
authors.affiliation: Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA; Mayo Clinic Cancer Center, Rochester, MN, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Lupu
keywords: CCN1; CYR61; breast cancer; fatty acid synthase; metastasis