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Tetra-methoxystilbene modulates ductal growth of the developing murine mammary gland

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Abstract

Extensive data suggest that estradiol contributes to the development of breast cancer by acting as a mitogen and exerting direct genotoxic effects after enzymatic conversion to 4-hydroxyestradiol (4-OHE2) via cytochrome P450 1B1 (CYP1B1). The mammary gland, ovary, and uterus all express CYP1B1. Overexpression of this enzyme has been associated with an increased risk of breast cancer and blockade might reduce this carcinogenic effect. For this reason, we conducted systematic in vitro and in vivo studies of a CYP1B1 inhibitor, TMS (2,3′,4,5′-tetramethoxystilbene). We found that TMS blocked the enzymatic conversion of radiolabeled estradiol to both 2-hydroxyestradiol (2-OHE2) and 4-OHE2, but did not inhibit Cyp1b1 message formation. In vivo studies using mass spectrometry showed that TMS inhibited formation of 2-OHE2 and 4-OHE2 and the resulting estrogen-DNA adducts. To examine its biologic actions in vivo, we investigated whether TMS could block the hyperplastic changes that occur in the developing breast of aromatase-transfected mice. We found that TMS induced a significant reduction of ductal structures in mice less than 6 months in age. In older mice, no reduction in breast morphology occurred. These latter studies uncovered unexpected estrogen agonistic actions of TMS at high doses, including a paradoxical stimulation of breast ductal structures and the endometrium. These studies suggest that the enzyme inhibitory properties of TMS, as well as the effects on developing breast, could implicate a role for TMS in breast cancer prevention, but only in low doses and on developing breast.

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Abbreviations

TMS:

2,4,3′,5′-Tetramethoxystilbene

CYP1A1:

Cytochrome P450 1A1

Cyp1a1:

Mouse cytochrome P450 1B1

CYP1B1:

Human cytochrome P450 1B1

Cyp1b1:

Mouse cytochrome P450 1B1

E2:

Estradiol

4-OHE2:

4-Hydroxyestradiol

2-OHE2:

2-Hydroxyestradiol

TDLU:

Terminal duct lobular units

TDSABs:

Tertiary ductal structures and alveolar buds

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Acknowledgments

This study was supported by grants from the Susan G. Komen Breast cancer foundation KG080267 (S. E. Aiyar), and the UVa. Cancer Center through The Women’s Oncology Research Fund and the NCI Cancer Center support grant P30 CA44579 (R.J. Santen). Core support at the Eppley Institute was provided by grant P30 CA36727 from the National Cancer Institute.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Taehyun Kim, Hoyong Park, Wei Yue, Ji-Ping Wang, Zhenguo Zhang, Richard J. Santen & Sarah E. Aiyar

  2. Department of Surgery, Pusan Paik Hospital, Inje University, Busan, South Korea

    Taehyun Kim

  3. Department of Surgery, Kyungpook National University Hospital, Daegu, South Korea

    Hoyong Park

  4. Department of Pathology, University of Virginia, Charlottesville, VA, 22908, USA

    Kristen A. Atkins

  5. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-6805, USA

    Eleanor G. Rogan & Ercole L. Cavalieri

  6. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Khalid S. Mohammad

  7. College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul, South Korea

    Sanghee Kim

Authors
  1. Taehyun Kim
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  2. Hoyong Park
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  3. Wei Yue
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  8. Ercole L. Cavalieri
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  9. Khalid S. Mohammad
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  10. Sanghee Kim
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  11. Richard J. Santen
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  12. Sarah E. Aiyar
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Corresponding author

Correspondence to Sarah E. Aiyar.

Additional information

Taehyun Kim, Hoyong Park contributed equally to this work.

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Kim, T., Park, H., Yue, W. et al. Tetra-methoxystilbene modulates ductal growth of the developing murine mammary gland. Breast Cancer Res Treat 126, 779–789 (2011). https://doi.org/10.1007/s10549-010-1301-5

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  • DOI: https://doi.org/10.1007/s10549-010-1301-5

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