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Fatty acid synthase phosphorylation: a novel therapeutic target in HER2-overexpressing breast cancer cells

Quanri Jin1, Linda X Yuan, Delphine Boulbes

  • 1Department of Breast Medical Oncology, The University of Texas M, D, Anderson Cancer Center, Houston, TX 77030, USA. qjin@mdanderson.org

Breast Cancer Research : BCR
|November 18, 2010
PubMed
Abstract

Insights

Fatty acid synthase (FASN) phosphorylation by human epidermal growth factor receptor 2 (HER2) drives breast cancer progression. Inhibiting this interaction with lapatinib or C75 may offer a novel therapeutic strategy for HER2-overexpressing breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Human epidermal growth factor receptor 2 (HER2) is a key target in breast cancer therapy.
  • HER2 overexpression enhances fatty acid synthase (FASN) translation, promoting cell growth.
  • The precise molecular mechanisms regulating HER2 and FASN interaction remain unclear.

Purpose of the Study:

  • To investigate the hypothesis that HER2 directly phosphorylates FASN.
  • To elucidate the role of FASN phosphorylation in breast cancer progression.
  • To explore the therapeutic potential of targeting the HER2-FASN interaction.

Main Methods:

  • Mass spectrometry identified FASN as a lapatinib-dephosphorylated protein in SKBR3 cells.
  • Immunofluorescence, immunoprecipitation, Western blotting, and kinase assays were employed.
  • FASN enzymatic activity, invasion, and cell viability assays were conducted using SKBR3 and BT474 cells.

Main Results:

  • FASN was found to be phosphorylated when complexed with HER2.
  • Heregulin induced FASN phosphorylation and increased its enzymatic activity in HER2-overexpressing cells.
  • Lapatinib and the FASN inhibitor C75 blocked FASN phosphorylation and activity, inhibiting matrix metallopeptidase 9 and cell invasion.

Conclusions:

  • FASN phosphorylation by HER2 is a critical factor in breast cancer progression.
  • Targeting FASN phosphorylation by HER2 presents a potential novel therapeutic strategy.
  • This interaction is particularly relevant in HER2-overexpressing breast cancers.

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