Dietary γ-Tocopherol-Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response, and PPARγ.

Abstract

This study evaluated the anticancer activity and mechanism of action of a γ-tocopherol-rich tocopherol mixture, γ-TmT, in two different animal models of estrogen-induced breast cancer. The chemopreventive effect of γ-TmT at early (6 weeks), intermediate (18 weeks), and late (31 weeks) stages of mammary tumorigenesis was determined using the August-Copenhagen Irish rat model. Female rats receiving 17β-estradiol (E2) implants were administered with different doses (0%, 0.05%, 0.1%, 0.3%, and 0.5%) of γ-TmT diet. Treatment with 0.3% and 0.5% γ-TmT decreased tumor volume and multiplicity. At 31 weeks, serum concentrations of E2 were significantly decreased by γ-TmT. γ-TmT preferentially induced expression of the E2-metabolizing enzyme CYP1A1, over CYP1B1 in the rat mammary tissues. Nrf2-dependent antioxidant response was stimulated by γ-TmT, as evident from enhanced expression of its downstream targets, NQO1, GCLM, and HMOX1. Serum concentrations of the oxidative stress marker, 8-isoprostane, were also decreased in the γ-TmT-treated groups. Treatment with γ-TmT increased expression of PPARγ and its downstream genes, PTEN and p27, whereas the cell proliferation marker, PCNA, was significantly reduced in γ-TmT-treated mammary tumors. In an orthotopic model in which human MCF-7 breast cancer cells were injected into the mammary fat pad of immunodeficient mice, γ-TmT inhibited E2-dependent tumor growth at all the doses tested. In conclusion, γ-TmT reduced mammary tumor development, in part through decreased E2 availability and reduced oxidative stress in mammary tissues; γ-TmT could thus be an effective agent for the prevention and treatment of E2-induced breast cancer.

• Authors: Soumyasri Das Gupta, Sudathip Sae-tan, Joseph Wahler, Jae Young So, Min Ji Bak, Larry C Cheng, Mao-Jung Lee, Yong Lin, Weichung Joe Shih, James D Shull, Stephen Safe, Chung S Yang, Nanjoo Suh
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 8 Issue 9 Pg. 807-16 (Sep 2015) ISSN: 1940-6215 [Electronic] United States
• PMID: 26130252 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antioxidants
• Cdkn1b protein, rat
• Estrogens
• PPAR gamma
• Proliferating Cell Nuclear Antigen
• RNA, Messenger
• Cyclin-Dependent Kinase Inhibitor p27
• 8-epi-prostaglandin F2alpha
• Estradiol
• gamma-Tocopherol
• Dinoprost
• PTEN Phosphohydrolase
• Pten protein, rat

Topics

• Animals
• Antioxidants (metabolism)
• Cell Line, Tumor
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Dinoprost (analogs & derivatives, chemistry)
• Estradiol (administration & dosage)
• Estrogens (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoenzyme Techniques
• Immunohistochemistry
• MCF-7 Cells
• Mammary Glands, Animal (metabolism)
• Mammary Neoplasms, Animal (prevention & control)
• Mammary Neoplasms, Experimental (prevention & control)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Oxidative Stress
• PPAR gamma (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Proliferating Cell Nuclear Antigen (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Time Factors
• gamma-Tocopherol (therapeutic use)