The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells

Javier A. Menendez1,2, Luciano Vellon3, Ingrid Espinoza4,5, Ruth Lupu6,7

1ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Catalonia, Spain

2Girona Biomedical Research Institute (IDIBGI), Girona, Spain

3IBYME, CONICET-Laboratorio de Immunohematología, Buenos Aires, Argentina

4Cancer Institute, University of Mississippi, Jackson, MS, USA

5Department of Preventive Medicine, University of Mississippi, Jackson, MS, USA

6Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA

7Mayo Clinic Cancer Center, Rochester, MN, USA

Correspondence to:

Ruth Lupu, email: lupu.ruth@mayo.edu

Javier A. Menendez, email: jmenendez@idibgi.org; jmenendez@iconcologia.net

Keywords: CCN1, CYR61, fatty acid synthase, breast cancer, metastasis

Received: April 05, 2016     Accepted: July 08, 2016     Published: July 22, 2016


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 FASN-dependent 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.

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