Studies with animal models in vivo as well as with animal and human tumor cells in vitro suggest that specific fatty acids could reduce breast tumorigenesis. The most striking dietary fatty acid studies in animal models that show promise for reduction of breast cancer risk in humans are with conjugated linoleic acids (CLA) and n-3 fatty acids. Although a number of mechanisms have been proposed, the specific target of those fatty acids is not yet known. We sought to determine whether the effects of those fatty acids on terminally differentiated tumor cell seen could be due to alteration of breast cancer stem cells. The isomers, cis9, trans11-CLA and trans10, cis12-CLA, and the n-3 fatty acids, docosahexaenoic and eicosapentaenoic, reduced the proliferation of, and had increased toxicity towards, mammary tumor initiating cells. One mechanism involved in the effect of n-3 fatty acids may be due to alteration of the profile of prostaglandins. These results indicate that select fatty acids may be useful for preventing or reducing the risk of breast cancer as they may target the tumor initiating cell.
"Third, HADHA occupies an important position in the network of genes that have been implicated in autophagy and apoptosis . Finally, triangulation of the following facts lends additional credence to our observations: i) intact epithelium of mammary glands has the ability to act as stem cells for carcinogenesis ; ii) n-3 long chain fatty acids have the ability to target such stem cells ; and iii) HADHA is involved in the mitochondrial β-oxidation of long chain fatty acids. Together these observations from published literature strongly support the biological plausibility of our finding that HADHA is differentially expressed in subjects with and without breast cancer. "
[Show abstract][Hide abstract] ABSTRACT: The role of n-3 fatty acids in prevention of breast cancer is well recognized, but the underlying molecular mechanisms are still unclear. In view of the growing need for early detection of breast cancer, Graham et al. (2010) studied the microarray gene expression in histologically normal epithelium of subjects with or without breast cancer. We conducted a secondary analysis of this dataset with a focus on the genes (n = 47) involved in fat and lipid metabolism. We used stepwise multivariate logistic regression analyses, volcano plots and false discovery rates for association analyses. We also conducted meta-analyses of other microarray studies using random effects models for three outcomes--risk of breast cancer (380 breast cancer patients and 240 normal subjects), risk of metastasis (430 metastatic compared to 1104 non-metastatic breast cancers) and risk of recurrence (484 recurring versus 890 non-recurring breast cancers).
The HADHA gene [hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit] was significantly under-expressed in breast cancer; more so in those with estrogen receptor-negative status. Our meta-analysis showed an 18.4%-26% reduction in HADHA expression in breast cancer. Also, there was an inconclusive but consistent under-expression of HADHA in subjects with metastatic and recurring breast cancers.
Involvement of mitochondria and the mitochondrial trifunctional protein (encoded by HADHA gene) in breast carcinogenesis is known. Our results lend additional support to the possibility of this involvement. Further, our results suggest that targeted subset analysis of large genome-based datasets can provide interesting association signals.
BMC Research Notes 01/2012; 5(1):25. DOI:10.1186/1756-0500-5-25
[Show abstract][Hide abstract] ABSTRACT: Epidemiological and experimental studies have convincingly demonstrated that n-3 polyunsaturated fatty acids (PUFAs) inhibit the initiation and progression stages of colorectal cancer. Attenuation of cell proliferation and induction of apoptosis by modulation of multiple signaling pathways makes n-3 PUFAs a promising candidate for chemoprevention as well as a dietary adjuvant with other anticancer strategies. These PUFAs maintain intestinal homeostasis by regulating stem cell proliferation mediated through downregulation of Wnt signaling and upregulation of transforming growth factor β mediated signaling events. In addition, owing to their anti-inflammatory nature, these fatty acids also affect the intestinal milieu which has a critical role in maintaining the number of stem cells and their differentiation.
Current Colorectal Cancer Reports 12/2012; 8(4). DOI:10.1007/s11888-012-0145-2
[Show abstract][Hide abstract] ABSTRACT: Conjugated linoleic acids (CLA) are a group of polyunsaturated fatty acids (PUFA) with a single pair of conjugated double bonds. The major natural CLA isomer is 18:2 cis-9, trans-11 (c9, t11) linoleic acid, or rumenic acid (RA). Chemically synthesized CLA is also available, mostly as a mixture of RA and 18:2 trans-10, cis-12 (t10, c12) isomers in equal amounts (50:50). Consumption of ruminant meat (beef and lamb) and dairy products (milk and cheese) is the main source of dietary exposure to CLA. Despite numerous studies on animal and human models (tumorigenesis, obesity, immune response) it has not been established whether additional supplementation of CLA is of benefit. Moreover, some studies, conducted both in animals and in humans, reveal that CLA isomers may induce insulin resistance. Presently, balanced diet rich in CLA from natural sources is recommended. The purpose of this review was to sum up the results available in the literature.
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