ROLE RAS/MAPK PATHWY IN MAM CANC PROMOT BY LINOLEIC ACID

Project: Research project

Project Details

Description

Experiments are proposed to investigate the role of the Ras-mitogen
activated protein kinase (MAPK) signal transduction pathway in
mediating the mammary cancer promotional activity of Linoleic acid
(LA), a prominent fatty acid present in the typical Western type diets.
We have observed that, compared to a low fat diet, feeding a LA-rich,
corn oil-based high fat diet resulted in a significant increase in the
number of N-methyl-N-nitrosourea (MNU)-induced rat mammary
carcinomas without a Ha-ras codon 12 G A mutation (wild type at
codon 12, abbreviated as Wtras 12), but no change of those with the
mutation (mras12). We hypothesize that LA or its metabolites exert
this selective promotional effect through interactions with the Ras-
MAPK pathway. AIM 1 will test the hypothesis that LA or its
metabolites promote mammary carcinogenesis through an upregulation
of the expression of Raf-1 and MAPKK2 and the resulting MAPK
activation. AIM 2 will test the hypothesis that LA or its metabolites
(e.g., phosphatidic acids) enhance the in vivo Ras activity by
interfering with the Ras/GAP interaction and the increased in vivo Ras
activity accounts for MAPK activation and cancer promotion. The in
vivo approaches proposed include examining the effect of increasing
LA intake on MNU-induced carcinogenesis and the expression of the
MAPK cascade components; effect of intraductal infusion of LA or its
metabolites into mammary glands on Ras and MAPK activities, and
gene transcriptional regulation; and the effect of retroviral mediated
Raf-1 gene transfer on MNU-induced carcinogenesis.

The high fat-human breast cancer connection is highly controversial,
yet animal studies have consistently shown a mammary cancer
promotional activity of high fat diets rich in LA. The research in this
proposal may provide a strong rationale for a paradigm shift in fat-
associated cancer risk assessment to be based on the intake of specific
fatty acids, rather than of total fat, and the pathogenetic pathways that
initiate and promote cancer development. If our hypothesis is valid
and is extrapolatable to human carcinogenesis, a strong justification
can be made for recommending that specific populations of individuals
at risk for breast cancer modify their fat consumption pattern or
reduce fat intake to achieve gene/pathway-specific prevention.
StatusFinished
Effective start/end date5/16/974/30/98