A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein

Chi Tze Tiong, Chen Chen, Shi Jun Zhang, Jun Li, Anatoly Soshilov, Michael S. Denison, Lawrence Soon U Lee, Vincent H. Tam, Shih Peng Wong, H. Eric Xu, Eu Leong Yong

Research output: Contribution to journalArticle

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Abstract

There is concern that ingestion of dietary phytoestrogens may increase risk of estrogen receptor alpha (ERα)-positive breast cancer. The prenylflavone icaritin, a phytoestrogen consumed in East Asian societies for its perceived beneficial effects on bone health, stimulated the growth of breast cancer (MCF-7) cells at low concentrations. Although acting like an estrogenic ligand, icaritin exerted an unexpected suppressive effect on estrogen-stimulated breast cancer cell proliferation and gene expression at higher concentrations. Like estradiol, icaritin could dose-dependently destabilize ERα protein. However, destabilization of ERα by the estradiol/icaritin combination was profound and greater than that observed for either compound alone. Microarray gene expression analyses implicated aryl hydrocarbon receptor (AhR) signaling for this suppressive effect of icaritin. Indeed, icaritin was an AhR agonist that competitively reduced specific binding of a potent AhR agonist and increased expression of the AhR-regulated gene CYP1A1. When AhR was knocked down by small interfering RNA, the suppressive effect of icaritin on estradiol-stimulated breast cancer cell growth and gene expression was abolished, and ERα protein stability was partially restored. Similarly in an athymic nude mouse model, icaritin restricted estradiol-stimulated breast cancer xenograft growth and strongly reduced ERα protein levels. Overall, our data support the feasibility for the development of dual agonists like icaritin, which are estrogenic but yet, through activating AhR-signaling, can destabilize ERα protein to restrict ERα-positive breast cancer cell growth.

Original languageEnglish (US)
Pages (from-to)1089-1097
Number of pages9
JournalCarcinogenesis
Volume33
Issue number5
DOIs
StatePublished - 2012

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Aryl Hydrocarbon Receptors
Estrogen Receptor alpha
Breast Neoplasms
Growth
Estradiol
Phytoestrogens
Gene Expression
Nude Mice
icaritin
estrophilin
Cytochrome P-450 CYP1A1
Protein Stability
MCF-7 Cells
Heterografts
Small Interfering RNA
Estrogens
Eating
Cell Proliferation
Ligands
Bone and Bones

ASJC Scopus subject areas

  • Cancer Research

Cite this

Tiong, C. T., Chen, C., Zhang, S. J., Li, J., Soshilov, A., Denison, M. S., ... Yong, E. L. (2012). A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein. Carcinogenesis, 33(5), 1089-1097. https://doi.org/10.1093/carcin/bgs110

A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein. / Tiong, Chi Tze; Chen, Chen; Zhang, Shi Jun; Li, Jun; Soshilov, Anatoly; Denison, Michael S.; Lee, Lawrence Soon U; Tam, Vincent H.; Wong, Shih Peng; Xu, H. Eric; Yong, Eu Leong.

In: Carcinogenesis, Vol. 33, No. 5, 2012, p. 1089-1097.

Research output: Contribution to journalArticle

Tiong, CT, Chen, C, Zhang, SJ, Li, J, Soshilov, A, Denison, MS, Lee, LSU, Tam, VH, Wong, SP, Xu, HE & Yong, EL 2012, 'A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein', Carcinogenesis, vol. 33, no. 5, pp. 1089-1097. https://doi.org/10.1093/carcin/bgs110
Tiong, Chi Tze ; Chen, Chen ; Zhang, Shi Jun ; Li, Jun ; Soshilov, Anatoly ; Denison, Michael S. ; Lee, Lawrence Soon U ; Tam, Vincent H. ; Wong, Shih Peng ; Xu, H. Eric ; Yong, Eu Leong. / A novel prenylflavone restricts breast cancer cell growth through AhR-mediated destabilization of ERα protein. In: Carcinogenesis. 2012 ; Vol. 33, No. 5. pp. 1089-1097.
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