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

Taehyun Kim, Hoyong Park, Wei Yue, Ji Ping Wang, Kristen A. Atkins, Zhenguo Zhang, Eleanor G. Rogan, Ercole L. Cavalieri, Khalid S. Mohammad, Sanghee Kim, Richard J. Santen, Sarah E. Aiyar

Research output: Contribution to journalArticle

13 Scopus citations

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′-tetramethoxystil-bene). 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.

Original languageEnglish (US)
Pages (from-to)779-789
Number of pages11
JournalBreast Cancer Research and Treatment
Volume126
Issue number3
DOIs
StatePublished - Apr 2011

Keywords

  • 2,3′,4,5′-tetramethoxystilbene (TMS)
  • Aromatase-transgenic mice
  • Cytochrome P450 1B1
  • Ductal branching
  • Mouse mammary gland

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kim, T., Park, H., Yue, W., Wang, J. P., Atkins, K. A., Zhang, Z., Rogan, E. G., Cavalieri, E. L., Mohammad, K. S., Kim, S., Santen, R. J., & Aiyar, S. E. (2011). Tetra-methoxystilbene modulates ductal growth of the developing murine mammary gland. Breast Cancer Research and Treatment, 126(3), 779-789. https://doi.org/10.1007/s10549-010-1301-5