Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma.
OBJECTIVE
Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in gamma- and delta-tocopherols against mammary tumorigenesis.


METHODS
Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells.


RESULTS
Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer.


CONCLUSIONS
The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.
Lee
Hong Jin
HJ
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
Ju
Jihyeung
J
Paul
Shiby
S
So
Jae-Young
JY
DeCastro
Andrew
A
Smolarek
Amanda
A
Lee
Mao-Jung
MJ
Yang
Chung S
CS
Newmark
Harold L
HL
Suh
Nanjoo
N
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008770:Methylnitrosourea / Q000633:toxicity; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D024505:Tocopherols / Q000008:administration & dosage* / Q000737:chemistry; D014815:Vitamins / Q000008:administration & dosage* / Q000737:chemistry; D020741:rho GTP-Binding Proteins / Q000819:agonists / Q000378:metabolism
D000477:Alkylating Agents; D016588:Anticarcinogenic Agents; D047495:PPAR gamma; D018809:Proliferating Cell Nuclear Antigen; D014815:Vitamins; C413374:p27 antigen; D008770:Methylnitrosourea; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D020741:rho GTP-Binding Proteins; D024505:Tocopherols