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. 2015 Sep;8(9):807-16.
doi: 10.1158/1940-6207.CAPR-15-0154. Epub 2015 Jun 30.

VSports在线直播 - Dietary γ-Tocopherol-Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response, and PPARγ

Soumyasri Das Gupta  1 , Sudathip Sae-tan  1 , Joseph Wahler  1 , Jae Young So  1 , Min Ji Bak  1 , Larry C Cheng  1 , Mao-Jung Lee  1 , Yong Lin  2 , Weichung Joe Shih  2 , James D Shull  3 , Stephen Safe  4 , Chung S Yang  5 , Nanjoo Suh  6
Affiliations

"V体育平台登录" Dietary γ-Tocopherol-Rich Mixture Inhibits Estrogen-Induced Mammary Tumorigenesis by Modulating Estrogen Metabolism, Antioxidant Response, and PPARγ

Soumyasri Das Gupta et al. Cancer Prev Res (Phila). 2015 Sep.

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 VSports手机版. 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. .

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Conflict of interest statement

Disclosure of potential conflicts of interest: No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
γ-TmT inhibits estrogen-induced mammary tumorigenesis in ACI rats. ACI rats implanted with E2 were fed with control diet or diet containing different doses of γ-TmT for 31 weeks (n=30/group). (A) The tumor-free survival curve of each group is shown. (B) Average tumor volume of the different treatment groups at 31 weeks is shown. (C) Average tumor multiplicity of each group at 31 weeks is shown. (D) Average body weights of each treatment group at 31 weeks are shown. P-values are compared to E2 control. Statistical significance, *P < 0.05, **P < 0.01.
Figure 2
Figure 2
γ-TmT reduces serum E2 levels and induces estrogen metabolizing enzyme CYP1A1 in E2-treated ACI rats. (A) Analysis of E2 levels in ACI rat serum at 6, 18 and 31 weeks (n=6/group for 6, 18 weeks; n=9/group for 31 weeks). (B) qPCR analysis of CYP1A1 and CYP1B1 mRNA expression in the mammary glands (6, 18 weeks), tumors (31 weeks) and liver (31 weeks) of ACI rats (n=6–8/group). Statistical significance, *P < 0.05, **P < 0.01, ***P < 0.001. (C) Western blot analysis of CYP1A1 and CYP1B1 in the mammary tumors of ACI rats at 31 weeks (n=3/group).
Figure 3
Figure 3
γ-TmT induces Nrf2-mediated antioxidant response and reduces serum 8-isoprostane in E2-treated ACI rats. (A) qPCR analysis of mRNA expression of Nrf2 and its downstream targets, NQO1, GCLM and HMOX1, in rat mammary glands (6 and 18 weeks) and mammary tumors (31 weeks) (n=6–8/group). (B) Western blot analysis of Nrf2, NQO1, GCLM and HMOX1 in the mammary tumors of ACI rats at 31 weeks (n=3/group). (C) Analysis of the 8-isoprostane levels in the serum of ACI rats at 6, 18 and 31 weeks (n=6/group). Statistical significance, *P < 0.05, ***P < 0.001.
Figure 4
Figure 4
γ-TmT regulates nuclear receptor signaling and cell proliferation in E2-treated ACI rats. (A) qPCR analysis of mRNA expression of ERβ, PPARγ, PTEN, and p27 in the mammary glands (6 and 18 weeks) and mammary tumors (31 weeks) of ACI rats (n=6–8/group). (B) Representative images of PCNA staining in the mammary tumors of ACI rats (40X magnification). The scale bar represents 50 μm. Quantification of nuclear PCNA staining in the mammary tumors (n=3/group) is shown. Statistical significance, *P < 0.05, **P < 0.01.
Figure 5
Figure 5
γ-TmT inhibits E2-induced mammary tumor growth in MCF-7 xenografted mice. Nu/nu mice were implanted with E2 pellets (0.72 mg). After 2 days, MCF-7 cells were injected into the mammary fat pad of the mice. From the day of MCF-7 cell injection, mice were fed with control diet or different doses of γ-TmT diet for 9 weeks (n=10/group). (A) Average tumor volume at weekly time points for the different treatment groups is shown. (B) Average tumor weight at 9 weeks is shown. Statistical significance, *P < 0.05, **P < 0.01.
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