We identified MEK4 as a proinvasion protein in six human prostate cancer cell lines and the target for genistein. We showed, to our knowledge for the first time, that genistein treatment, compared with no treatment, was associated with decreased levels of MMP-2 transcripts in normal prostate cells from prostate cancer-containing tissue.

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Background-Diets containing omega-3 fat have been associated with decreased tumor development in the colon, breast, and prostate. We assessed the effects of a diet rich in omega-3 (ω-3) fat on the development of pancreatic precancer in elastase (EL)-Kras transgenic mice and examined the effect of an ω-3 fatty acid on pancreatic cancer cells in vitro.

Diets containing omega-6 (x-6) fat have been associated with increased tumor development in carcinogen-induced pancreatic cancer models. However, the effects of x-6 fatty acids and background strain on the development of genetically-induced pancreatic neoplasia is unknown. We assessed the effects of a diet rich in x-6 fat on the development of pancreatic neoplasia in elastase (EL)-Kras G12D (EL-Kras) mice in two different backgrounds. EL-Kras FVB mice were crossed to C57BL/6 (B6) mice to produce EL-Kras FVB6 F1 (or EL-Kras F1) and EL-Kras B6 congenic mice. Age-matched EL-Kras mice from each strain were compared to one another on a standard chow. Two cohorts of EL-Kras FVB and EL-Kras F1 mice were fed a 23% corn oil diet and compared to age-matched mice fed a standard chow. Pancreata were scored for incidence, frequency, and size of neoplastic lesions, and stained for the presence of mast cells to evaluate changes in the inflammatory milieu secondary to a high fat diet. EL-Kras F1 mice had increased incidence, frequency, and size of pancreatic neoplasia compared to EL-Kras FVB mice. The frequency and size of neoplastic lesions and the weight and pancreatic mast cell densities in EL-Kras F1 mice were increased in mice fed a high x-6 fatty acid diet compared to mice fed a standard chow. We herein introduce the EL-Kras B6 mouse model which presents with increased frequency of pancreatic neoplasia compared to EL-Kras F1 mice. The phenotype in EL-Kras F1 and FVB mice is promoted by a diet rich in x-6 fatty acid.Pancreatic adenocarcinoma is the fourth leading cause of cancer-related mortality in the U.S. 1 An estimated 34,290 deaths resulted from pancreatic cancer in 2008 alone. 1 Given the dismal mortality associated with pancreatic cancer, much attention has been given to the prevention of this deadly disease. Several risk factors have been identified with the aim of minimizing these factors for the purpose of prevention.Obesity is one such risk factor, which has been shown to increase the risk for pancreatic cancer in numerous prospective cohort studies. A body mass index (BMI) !30 was found to increase relative risk (RR) for pancreatic adenocarcinoma, with RR values ranging between 1.2 and 2.76. [2][3][4][5][6] However, the exact mechanisms that relate obesity to pancreatic cancer continue to be investigated.Fatty acid metabolism is an area of research that may help explain the tie between obesity and pancreatic cancer. Our lab previously found that omega-3 fatty acids have a chemopreventive role against the development of pancreatic neoplasia in a murine model. 7 In contrast, previous studies have shown that diets rich in x-6 fatty acids stimulated pancreatic tumor growth, in vitro and in vivo. 8,9 However, these studies have had conflicting explanations for mechanism. In vitro evidence argued for increased proliferation rates due to x-6 fatty acids while in vivo studies found no difference in proliferation rates. Furthermore, nearly all related animal studies utilized carcinogen-induced invasive pancreatic adenoc...

Pancreatic cancer remains a daunting foe despite a vast number of accumulating molecular analyses regarding the mutation and expression status of a variety of genes. Indeed, most pancreatic cancer cases uniformly present with a mutation in the KRAS allele leading to enhanced RAS activation. Yet our understanding of the many epigenetic/environmental factors contributing to disease incidence and progression is waning. Epidemiologic data suggest that diet may be a key factor in pancreatic cancer development and potentially a means of chemoprevention at earlier stages. While diets high in ω3 fatty acids are typically associated with tumor suppression, diets high in ω6 fatty acids have been linked to increased tumor development. Thus, to better understand the contribution of these polyunsaturated fatty acids to pancreatic carcinogenesis, we modeled early stage disease by targeting mutant KRAS to the exocrine pancreas and administered diets rich in these fatty acids to assess tumor formation and altered cell-signaling pathways. We discovered that, consistent with previous reports, the ω3-enriched diet led to reduced lesion penetrance via repression of proliferation associated with reduced phosphorylated AKT (pAKT), whereas the ω6-enriched diet accelerated tumor formation. These data provide a plausible mechanism underlying previously observed effects of fatty acids and suggest that administration of ω3 fatty acids can reduce the pro-survival, pro-growth functions of pAKT. Indeed, counseling subjects at risk to increase their intake of foods containing higher amounts of ω3 fatty acids could aid in the prevention of pancreatic cancer.