The impact of fish oil on the chemopreventive efficacy of tamoxifen against development of N-methyl-N-nitrosourea-induced rat mammary carcinogenesis.
The antiestrogen tamoxifen reduces breast cancer incidence in high-risk women but is unable to inhibit the development of hormone-independent tumors. Omega-3 polyunsaturated fatty acids (n-3 PUFA), known ligands of the peroxisome proliferator activated receptor-gamma (PPARgamma), generally exert tumor-suppressive effects. Based on the known crosstalk between the estrogen and the PPARgamma receptors, we tested the hypothesis that the combination of tamoxifen with n-3 PUFA results in a superior antitumor action over the individual interventions. In this study, we report for the first time that the combination of a fish oil diet rich in n-3 PUFA and tamoxifen seemed to inhibit N-methyl-N-nitrosourea-induced mammary carcinogenesis, tumor multiplicity, and volume to a greater extent than the individual interventions. The potential superiority of the combination was particularly evident at a suboptimal dose of tamoxifen, which, by itself, was unable to significantly decrease tumor development. Because activation of PPARgamma is known to inhibit oxidative stress, we examined the effects of our interventions on circulating and tumor levels of glutathione, a major intracellular antioxidant. Our results indicate that reduction in the level of oxidative stress may be a potential mechanism by which the n-3 PUFA-rich diet potentiated the tumor-suppressive effect of tamoxifen. Our interventions were well tolerated without evidence of toxicity. Combined administration of tamoxifen and n-3 PUFA is a promising new approach to breast cancer prevention. Because of its safety, this combination can quickly be translated to the clinic if its superiority can be supported by future studies.
Manni
Andrea
A
Division of Endocrinology, Hershey Medical Center, 500 University Drive, Hershey, PA 17033, USA. amanni@hmc.psu.edu
Xu
Haifang
H
Washington
Sharlene
S
Aliaga
Cesar
C
Cooper
Timothy
T
Richie
John P
JP
Bruggeman
Richard
R
Prokopczyk
Bogdan
B
Calcagnotto
Ana
A
Trushin
Neil
N
Mauger
David
D
Verderame
Michael F
MF
El-Bayoumy
Karam
K
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005395:Fish Oils / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000627:therapeutic use*
D000477:Alkylating Agents; D018931:Antineoplastic Agents, Hormonal; D005227:Fatty Acids; D005395:Fish Oils; D013629:Tamoxifen; D008770:Methylnitrosourea