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

Jin Lee Hong, Jihyeung Ju, Shiby Paul, Jae Young So, Andrew DeCastro, Amanda Smolarek, Mao Jung Lee, Chung S. Yang, Harold L. Newmark, Nanjoo Suh

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Purpose: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms,which are the α, β, γ, and δ 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 γ- and δ-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 γ- and δ-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-γ, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated peroxisome proliferator activated receptor-γ and antagonized estrogen action in breast cancer. Conclusion: The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer.

Original languageEnglish (US)
Pages (from-to)4242-4249
Number of pages8
JournalClinical Cancer Research
Volume15
Issue number12
DOIs
StatePublished - Jun 15 2009

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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