Free fatty acids enhance breast cancer cell migration through plasminogen activator inhibitor-1 and SMAD4.

Academic Article


  • Obesity is a risk factor for breast cancer and is associated with increased plasma concentrations of free fatty acids (FFAs). We and others have demonstrated that FFA induces plasminogen activator inhibitor-1 (PAI-1) expression in a variety of cells. Emerging evidence supports elevation of PAI-1 as a prognostic marker for breast cancer. Therefore, we hypothesized that FFAs might increase expression of PAI-1 in breast cancer cells and facilitate breast cancer progression. Secreted PAI-1 was higher in invasive and metastatic MDA-MB-231 cells compared with less invasive and non-metastatic Hs578T cells. Utilizing FFAs with different saturation and chain lengths, we demonstrated that linoleic acid induced expression of PAI-1 in MDA-MB-231 cells. Linoleic acid also induced in vitro migration of MDA-MB-231. By contrast, other FFAs tested had little or no effect on PAI-1 expression or migration. Linoleic acid-induced breast cancer cell migration was completely inhibited by virally expressed antisense PAI-1 RNA. Furthermore, increased expression of PAI-1 by FFAs was not detected in the SMAD4-deficient MDA-MB-468 breast carcinoma cells. Electrophoretic mobility-shift assay confirmed that linoleic acid-induced expression of PAI-1 was mediated, at least in part, by SMAD4 in MDA-MB-231 cells. That linoleic acid induces PAI-1 expression in breast cancer cells through SMAD4 provides a novel insight into understanding the relationships between two migration-associated molecules, FFAs, and PAI-1.
  • Published In


  • Breast Neoplasms, Cell Line, Tumor, Cell Movement, Fatty Acids, Nonesterified, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Neoplasm Invasiveness, Oligoribonucleotides, Antisense, Plasminogen Activator Inhibitor 1, RNA, Messenger, RNA, Neoplasm, Smad4 Protein
  • Digital Object Identifier (doi)

    Pubmed Id

  • 18101145
  • Author List

  • Byon CH; Hardy RW; Ren C; Ponnazhagan S; Welch DR; McDonald JM; Chen Y
  • Start Page

  • 1221
  • End Page

  • 1228
  • Volume

  • 89
  • Issue

  • 11