Pharmacological inhibition of fatty acid synthase (FAS): A novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her-2/neu (erbB-2) oncogene-induced malignant transformation

Javier A. Menendez, Inderjit Mehmi, Vishal A. Verma, Poh K. Teng, Ruth Lupu

Research output: Contribution to journalArticle

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Abstract

We designed our experiments to evaluate whether fatty acid synthase (FAS), a lipogenic enzyme linked to tumor virulence in population studies of human cancer, is necessary for the malignant transformation induced by Her-2/neu (erbB-2) oncogene, which is overexpressed not only in invasive breast cancer but also in premalignant atypical duct proliferations and in ductal carcinoma in situ of the breast. To avoid the genetic complexities associated with established breast cancer cell lines, we employed NIH-3T3 mouse fibroblasts engineered to overexpress human Her-2/ neu coding sequence. NIH-3T3/Her-2 cells demonstrated a significant upregulation of FAS protein expression, which was dependent on the upstream activation of mitogen-activated protein kinase and phosphatidylinositol 3′-kinase/ AKT pathways. Remarkably, pharmacological FAS blockade using the mycotoxin cerulenin or the novel small compound C75 completely suppressed the state of Her-2/neu-induced malignant transformation by inhibiting the ability of NIH-3T3/Her-2 cells to grow under either anchorage-independent (i.e., to form colonies in soft agar) or low-serum monolayer conditions. Moreover, NIH-3T3/Her-2 fibroblasts were up to three times more sensitive to chemical FAS inhibitors relative to untransformed controls as determined by MTT-based cell viability assays. In addition, pharmacological FAS blockade preferentially induced apoptotic cell death of NIH-3T3/Her-2 fibroblasts, as determined by an ELISA for histone-associated DNA fragments and by the terminal deoxynucleotidyltransferase (TdT)-mediated nick end labeling assay (TUNEL). Interestingly, the degree of Her-2/neu oncogene expression in a panel of breast cancer cell lines was predictive of sensitivity to chemical FAS inhibitors-induced cytotoxicity, while low-FAS expressing and chemical FAS inhibitors-resistant MDA-MB-231 breast cancer cells became hypersensitive to FAS blockade when they were engineered to overexpress Her-2/neu. Our observations strongly suggest that inhibition of FAS activity may provide a new molecular avenue for chemotherapeutic prevention and/or treatment of Her-2/neu-related breast carcinomas.

Original languageEnglish (US)
Pages (from-to)164-178
Number of pages15
JournalMolecular Carcinogenesis
Volume41
Issue number3
DOIs
StatePublished - Nov 2004
Externally publishedYes

Fingerprint

Fatty Acid Synthases
Chemoprevention
Oncogenes
Pharmacology
Breast Neoplasms
Therapeutics
Fibroblasts
Cerulenin
Phosphatidylinositol 3-Kinase
Cell Line
Carcinoma, Intraductal, Noninfiltrating
DNA Nucleotidylexotransferase
Mycotoxins
In Situ Nick-End Labeling
Mitogen-Activated Protein Kinases
Histones
Agar
Virulence
Neoplasms
Cell Survival

Keywords

  • Apoptosis
  • C75
  • Cerulenin
  • Chemoprevention
  • erbB-2
  • Fatty acid synthase
  • Her-2/neu
  • Transformation

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Pharmacological inhibition of fatty acid synthase (FAS) : A novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her-2/neu (erbB-2) oncogene-induced malignant transformation. / Menendez, Javier A.; Mehmi, Inderjit; Verma, Vishal A.; Teng, Poh K.; Lupu, Ruth.

In: Molecular Carcinogenesis, Vol. 41, No. 3, 11.2004, p. 164-178.

Research output: Contribution to journalArticle

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