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

Javier A. Menendez, Luciano Vellon, Ingrid Espinoza, Ruth Lupu

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)242-257
Number of pages16
JournalOncoscience
Volume3
Issue number7-8
DOIs
StatePublished - 2016

Fingerprint

Fatty Acid Synthases
Cysteine
Breast Neoplasms
Neoplasm Metastasis
Phenotype
Transcriptional Activation
Estrogens
Cerulenin
Pharmacology
Lipogenesis
Mycotoxins
MCF-7 Cells
Response Elements
Sterols
Tamoxifen
Oncogenes
Protein Binding
Disease Progression
Carrier Proteins
Binding Sites

Keywords

  • Breast cancer
  • CCN1
  • CYR61
  • Fatty acid synthase
  • Metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells. / Menendez, Javier A.; Vellon, Luciano; Espinoza, Ingrid; Lupu, Ruth.

In: Oncoscience, Vol. 3, No. 7-8, 2016, p. 242-257.

Research output: Contribution to journalArticle

Menendez, Javier A. ; Vellon, Luciano ; Espinoza, Ingrid ; Lupu, Ruth. / The metastasis inducer CCN1 (CYR61) activates the fatty acid synthase (FASN)-driven lipogenic phenotype in breast cancer cells. In: Oncoscience. 2016 ; Vol. 3, No. 7-8. pp. 242-257.
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