Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

CONCLUSION:

The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.

• Authors: Hong Jin Lee, Jihyeung Ju, Shiby Paul, Jae-Young So, Andrew DeCastro, Amanda Smolarek, Mao-Jung Lee, Chung S Yang, Harold L Newmark, Nanjoo Suh
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 12 Pg. 4242-9 (Jun 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19509159 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Alkylating Agents
• Anticarcinogenic Agents
• PPAR gamma
• Proliferating Cell Nuclear Antigen
• Vitamins
• p27 antigen
• Methylnitrosourea
• Proto-Oncogene Proteins c-akt
• Caspase 3
• rho GTP-Binding Proteins
• Tocopherols

Topics

• Alkylating Agents (pharmacology)
• Animals
• Anticarcinogenic Agents (administration & dosage, chemistry)
• Apoptosis
• Caspase 3 (drug effects, metabolism)
• Cell Line, Tumor
• Dietary Supplements
• Female
• Humans
• Mammary Neoplasms, Experimental (chemically induced, pathology, prevention & control)
• Methylnitrosourea (toxicity)
• PPAR gamma (agonists, metabolism)
• Proliferating Cell Nuclear Antigen (drug effects, metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Tocopherols (administration & dosage, chemistry)
• Vitamins (administration & dosage, chemistry)
• rho GTP-Binding Proteins (agonists, metabolism)