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.