Carcinogenesis Advance Access published online on October 13, 2009
Carcinogenesis, doi:10.1093/carcin/bgp243
Dietary olive oil and corn oil differentially affect experimental breast cancer through distinct modulation of the p21ras signaling and the proliferation-apoptosis balance
Department of Cell Biology, Physiology and Immunology, Medical Physiology Unit. Medicine School, Universitat Autònoma de Barcelona. 08193 Bellaterra, Barcelona, Spain
To whom corresponde should be addressed: Dr. Eduard Escrich., Department of Cell Biology, Physiology and Immunology, Medical Physiology Unit. Medicine School, Universitat Autònoma de Barcelona. 08193 Bellaterra, Barcelona (Spain). Telephone: 34 93 5811423 / Fax: 34 93 5812986, E-mail address: Eduard.Escrich{at}uab.es
Extra-virgin olive oil (EVOO) has been hypothesized to have chemopreventive effects on breast cancer, unlike high corn oil (HCO) diets which stimulate it. We have investigated mechanisms of these differential modulatory actions on experimental mammary cancer. In dimethylbenz(
)anthracene-induced breast adenocarcinomas of rats fed a high EVOO, HCO and control diets (n = 20 for each group), we have analyzed the expression and activity of ErbB receptors, p21Ras and its ERK1/2, Akt and RalA/B effectors by immunoblotting analyses. We explored the Ha-ras1 mutation status by Southern blot, MAMA and sequencing, and the HMG-CoA reductase and squalene synthase mRNA expression by Real Time-polymerase chain reaction (PCR). We analyzed the tumor mitotic index, PCNA levels, and apoptosis through Caspase-3 analysis and TUNEL assays. Finally, we measured the 8-oxo-2’-deoxyguanosine levels. Non-parametrical statistics were used. The EVOO diet decreased Ras activation, down-regulated the Ras/PI3K/Akt pathway and up-regulated the Raf/Erk pathway, compared to the control. In contrast, the HCO diet did not modify Ras activity but rather enhanced the Raf/Erk pathway. The EVOO diet decreased the cleaved ErbB4 levels, compared to the HCO diet, increased apoptosis and diminished the mono-ubiquitylated PCNA levels, which is related to DNA damage. Tumors from rats fed the EVOO diet displayed a more benign phenotype, whereas those from rats fed the HCO diet were biologically more aggressive. In conclusion, high EVOO and corn oil diets exert their modulatory effects on breast cancer through a different combination of Ras signaling pathways, a different proliferation/apoptosis balance and probably distinct levels of DNA damage.
Key Words: Breast cancer • corn oil • Mediterranean diet • olive oil • p21Ras cell signaling • apoptosis
Received July 8, 2009; revised September 23, 2009; accepted September 29, 2009.