title: Prevention of carcinogenesis and inhibition of breast cancer tumor burden by dietary stearate.
abstract: Previous studies have shown that stearate (C18:0), a dietary long-chain saturated fatty acid, inhibits breast cancer cell neoplastic progression; however, little is known about the mechanism modulating these processes. We demonstrate that stearate, at physiological concentrations, inhibits cell cycle progression in human breast cancer cells at both the G(1) and G(2) phases. Stearate also increases cell cycle inhibitor p21(CIP1/WAF1) and p27(KIP1) levels and concomitantly decreases cyclin-dependent kinase 2 (Cdk2) phosphorylation. Our data also show that stearate induces Ras- guanosine triphosphate formation and causes increased phosphorylation of extracellular signal-regulated kinase (pERK). The MEK1 inhibitor, PD98059, reversed stearate-induced p21(CIP1/WAF1) upregulation, but only partially restored stearate-induced dephosphorylation of Cdk2. The Ras/mitogen-activated protein kinase/ERK pathway has been linked to cell cycle regulation but generally in a positive way. Interestingly, we found that stearate inhibits both Rho activation and expression in vitro. In addition, constitutively active RhoC reversed stearate-induced upregulation of p27(KIP1), providing further evidence of Rho involvement. To test the effect of stearate in vivo, we used the N-Nitroso-N-methylurea rat breast cancer carcinogen model. We found that dietary stearate reduces the incidence of carcinogen-induced mammary cancer and reduces tumor burden. Importantly, mammary tumor cells from rats on a stearate diet had reduced expression of RhoA and B as well as total Rho compared with a low-fat diet. Overall, these data indicate that stearate inhibits breast cancer cell proliferation by inhibiting key check points in the cell cycle as well as Rho expression in vitro and in vivo and inhibits tumor burden and carcinogen-induced mammary cancer in vivo.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, 701 S. 19th Street, Birmingham, AL 35294, USA.
authors.forename: Chuanyu
authors.initials: C
authors.lastname: Li
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Zhao
authors.forename: Eric C
authors.initials: EC
authors.lastname: Toline
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Evans
authors.forename: Arig
authors.initials: A
authors.lastname: Ibrahim-Hashim
authors.forename: Renee A
authors.initials: RA
authors.lastname: Desmond
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hardy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D018752:Diet, Fat-Restricted; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013228:Stearates / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D013228:Stearates; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D020741:rho GTP-Binding Proteins