title: Free fatty acids enhance breast cancer cell migration through plasminogen activator inhibitor-1 and SMAD4.
abstract: 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.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, 1530 3rd Avenue South, 533 LHRB, Birmingham, AL 35294, USA. ybchen@uab.edu
authors.forename: Chang Hyun
authors.initials: CH
authors.lastname: Byon
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hardy
authors.forename: Changchun
authors.initials: C
authors.lastname: Ren
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
authors.forename: Danny R
authors.initials: DR
authors.lastname: Welch
authors.forename: Jay M
authors.initials: JM
authors.lastname: McDonald
authors.forename: Yabing
authors.initials: Y
authors.lastname: Chen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D009361:Neoplasm Invasiveness; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D005230:Fatty Acids, Nonesterified; D020320:Oligoribonucleotides, Antisense; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C497796:SMAD4 protein, human; D051901:Smad4 Protein