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 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.
Highlights
CCN1, known as CYR61, is an extracellular matrix-associated protein [1, 2] belonging to the Cysteine rich 61/Connective tissue growth factor/Nephroblastoma overexpressed (CCN) gene-family of survival and angiogenic regulators, which includes CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3) [3,4,5,6,7,8,9,10]
Estrogendependent MCF-7 breast cancer cells, which naturally express very low to undetectable levels of CCN1, were transfected with full-length CCN1 cDNA [16, 28] and stable cell clones were selected with zeocin
We reveal for the first time that fatty acid synthase (FASN), a key enzyme for endogenous fatty acid biogenesis whose overexpression is associated with more aggressive subsets of breast carcinomas and poorer clinical outcomes, constitutes part of the cellular signaling cascade orchestrated by CCN1 to drive breast cancer cell growth, angiogenesis and metastatic progression
Summary
CCN1, known as CYR61, is an extracellular matrix-associated protein [1, 2] belonging to the Cysteine rich 61/Connective tissue growth factor/Nephroblastoma overexpressed (CCN) gene-family of survival and angiogenic regulators, which includes CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3) [3,4,5,6,7,8,9,10]. TNBC accounts for a disproportionate number of metastatic disease cases and breast cancer deaths [23,24,25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
