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© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
RESPONSE: Re: Effect of 
-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene
Affiliations of authors: Fundació d'Investigació Biomèdica de Girona Dr. Josep Trueta and Institut Catalá d'Oncología de Girona-Hospital Universitari de Girona Dr. Josep Trueta, Girona, Catalonia, Spain (JAM); Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL (RL)
Correspondence to: Ruth Lupu, PhD, Evanston Northwestern Healthcare Research Institute, Department of Medicine, 1001 University Place, Evanston, IL 60201 (e-mail: r-lupu{at}northwestern.edu).
We welcome the correspondence by Dr. Das on our recent report that the 
-6 fatty acid (FA) 
-linolenic acid (GLA; 18:3n-6) transcriptionally suppresses the Her-2/neu oncogene (1). Although his molecular explanation for the synergism between GLA and trastuzumab is conceptually correct, it is unlikely that binding of GLA and/or its peroxidized products to DNA could explain this interaction.
Specifically, we do not agree with Das's suggestion that a general mechanism involving the generation of lipoperoxides probably explains Her-2/neu suppression by GLA. Oleic acid (OA; 18:1n-9), the main -9 FA in olive oil, is monounsaturated whereas GLA is polyunsaturated. Nevertheless, OA is molecularly equivalent to GLA in that it suppresses Her-2/neu and interacts synergistically with trastuzumab (2,3). Treatment with GLA or OA increases the expression of the transcriptional repressor PEA3 in Her-2/neu gene–amplified tumor cells, and an intact PEA3 DNA-binding site on the endogenous Her-2/neu promoter is essential for GLA- and OA-induced Her-2/neu repression. Thus, a PEA3 binding site–mutated sequence impairs GLA- or OA-induced transcriptional blockade of Her-2/neu, whereas this effect does not occur when a Simian virus 40 viral promoter controls Her-2/neu expression (1,3). FAs other than GLA and OA can also modulate Her-2/neu regardless of their saturation index, even in the presence of the antioxidant vitamin E (4).
Because the effect is independent of the saturation index, lipoperoxide generation is unlikely to underlie it. Indeed, inhibition of fatty acid synthase (FAS)–catalyzed de novo biogenesis of saturated FA similarly suppresses Her-2/neu overexpression and interacts synergistically with trastuzumab by inducing PEA3-dependent Her-2/neu repression (5). We have recently found that specific depletion of FAS protein after transient transfection with a small inhibitory RNA that targets the FAS gene strongly antagonizes the anti-Her-2/neu effects of GLA (Menendez JA, Lupu R: unpublished data). That is, GLA-induced inhibition of Her-2/neu promoter activity cannot occur in the absence of FAS. Considering the fact that GLA inhibits FAS efficiently (6), it is reasonable to suggest that FAS blockade is necessary and sufficient to promote Her-2/neu repression. In agreement with this assumption, bezafibrate, which blocks the activity of the rate-limiting enzyme of endogenous FA synthesis, acetyl-coenzyme A (CoA) carboxylase, did not reduce Her-2/neu promoter activity (Menendez JA, and Lupu RL: unpublished data). Conversely, the FAS substrate malonyl-CoA on its own statistically significantly decreased Her-2/neu promoter activity (Menendez JA, and Lupu R: unpublished data). Therefore, it appears that supraphysiological accumulation of malonyl-CoA, due to its reduced utilization by FAS in the presence of GLA, acts as an indicator of "cell fuel" availability that suppresses Her-2/neu via formation of inhibitory PEA3 protein–PEA3 DNA binding site complexes on the endogenous Her-2/neu promoter (Fig.1).
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Finally, Das suggests that enhanced generation of free radicals could explain the synergism of GLA and trastuzumab because Her-2/neu directly participates in antioxidative processes. Our studies coincide with this suggestion but go further with the finding of Zhang et al. (7) that trastuzumab-sensitive proteins involved in metabolic and detoxification pathways, including FAS, are highly expressed in Her-2/neu–positive breast cancer. In view of all these findings, we consider Her-2/neu to be an "energy sensor" that actively participates in the response of cancer cells to nongenotoxic metabolic stresses, thus opening a new molecular avenue in the management of Her-2/neu–overexpressing carcinomas.
REFERENCES
(1) Menendez JA, Vellon L, Colomer R, Lupu R. Effect of -linolenic acid on the transcriptional activity of the Her-2/neu (erbB-2) oncogene. J Natl Cancer Inst 2005;97:1611–5.
(2) Menendez JA, Vellon L, Colomer R, Lupu R. Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification. Ann Oncol 2005;16:359–71.
(3) Menendez JA, Papadimitropoulou A, Vellon L, Colomer R, Lupu R. A genomic explanation connecting "Mediterranean diet," olive oil and cancer: oleic acid, the main monounsaturated fatty acid of olive oil, induces formation of inhibitory "PEA3 transcription factor-PEA3 DNA binding site" complexes at the Her-2/neu (erbB-2) oncogene promoter in breast, ovarian and stomach cancer cells. Eur J Cancer 2006; Epub ahead of print (DOI: 10.1016/j.ejca.2005.10.1016).
(4) Menendez JA, Ropero S, Lupu R, Colomer R. Dietary fatty acids regulate the activation status of Her-2/neu (c-erbB-2) oncogene in breast cancer cells. Ann Oncol 2004;15:1719–21.
(5) Menendez JA, Vellon L, Mehmi I, Oza BP, Ropero S, Colomer R, Lupu R. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci USA 2004;101:10715–20.
(6) Menendez JA, Ropero S, Mehmi I, Atlas E, Colomer R, Lupu R. Overexpression and hyperactivity of breast cancer-associated fatty acid synthase (oncogenic antigen-519) is insensitive to normal arachidonic fatty acid-induced suppression in lipogenic tissues but it is selectively inhibited by tumoricidal 
-linolenic and -linolenic fatty acids: a novel mechanism by which dietary fat can alter mammary tumorigenesis. Int J Oncol 2004;24:1369–83.[ISI][Medline]
(7) Zhang D, Tai LK, Wong LL, Chiu LL, Sethi SK, Koay ES. Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer. Mol Cell Proteomics 2005;4:1686–96.
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-Linolenic Acid on the Transcriptional Activity of the Her-2/neu (erbB-2) Oncogene
J Natl Cancer Inst 2006 98: 718.
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