Molecular Identification of Potential Selective Estrogen Receptor Modulator (SERM) Like Properties of Phytoestrogens in the Human Breast Cancer Cell Line MCF-7

Abstract

Numerous epidemiologic studies revealed that ethnic populations with higher dietary intake of phytoestrogens have the lowest incidence for breast cancer. The molecular mechanisms which may be responsible for this cancer protective action of phytoestrogens are so far only barely characterised. There are some hints that phytoestrogens may act like selective estrogen receptor modulators (SERMs) on the breast. For this reason we have investigated potential SERM-like properties of the phytoestrogens daidzein (Dai), coumestrol (Cou), and genistein (Gen) in the human breast cancer cell line MCF-7. Effects of these substances on progesterone (PR) and estrogen receptor α  (ER) mRNA expression and estrogen receptor α protein levels were studied in comparison to estradiol (E2) and the synthetic SERMs raloxifene (Ral) and faslodex (ICI 182 780). PR mRNA expression was up-regulated after administration of Cou, whereas treatment with Dai and Gen induced only a faint increase. ER mRNA expression was down-regulated by Cou but not affected by Dai and Gen. The content of ER protein in the breast cancer cells was strongly decreased by Gen, only a faint reduction could be observed following administration of Cou, whereas administration of Dai slightly increases ER protein levels. In summary and in comparison to the effects observed after administration of E2, Ral, and ICI it turned out that Cou shows molecular properties which are very similar to an estrogen receptor agonist like E2, whereas the molecular properties of Gen are comparable to the SERMs ICI and Ral. These results clearly indicate that phytoestrogens differ significantly in regard to their molecular action on breast cancer cells and can be subdivided into distinct functional categories.

Abbreviations

ER:estrogen receptor

PR:progesterone receptor

ICI:faslodex (ICI 182780)

Ral:raloxifene

SERM:selective estrogen receptor modulator

Dai:daidzein

Cou:coumestrol

Gen:genistein

E2:estradiol

SERM - coumestrol - daidzein - genistein - MCF-7 cell - phytoestrogen

References

• 1 Adlercreutz H. Epidemiology of phytoestrogens. Baillieres Clin. Endocrinol.  Metab.. 1998;  12 605-23
• 2 Santell R C, Kieu N, Helferich W G. Genistein inhibits growth of estrogen-independent human breast cancer cells in culture but not in athymic mice. J.  Nutr.. 2000;  130 1665-9
• 3 Dhingra K. Anti-estrogens - tamoxifen, SERMs and beyond. Invest.  New Drugs. 1999;  17 285-311
• 4 Wakeling A E, Dukes M, Bowler J. A potent specific pure anti-estrogen with clinical potential.  Cancer Res.. 1991;  51 3867-73
• 5 Jordan V C, Morrow M. Should clinicians be concerned about the carcinogenic potential of tamoxifen? Eur. J.  Cancer. 1994;  30 1714-21
• 6 Jaiyesimi I A, Buzdar A U, Decker D A, Hortobagyi G N. Use of tamoxifen for breast cancer: twenty-eight years later. J. Clin.  Oncol.. 1995;  13 513-29
• 7 Wakeling A E. A new approach to breast cancer therapy - Total estrogen ablation with pure anti-estrogen. In : Jordan VC (ed) Long-Term Tamoxifen Treatment for Breast Cancer. Madison W, University of Wisconsin 1994: 219-34
• 8 Dowsett M, Johnston S R, Iveson T J, Smith I E. Response to specific anti-oestrogen (ICI182780) in tamoxifen-resistant breast cancer.  Lancet. 1995;  345 8948
• 9 Turner C H, Sato M, Bryant H U. Raloxifene preserves bone strength and bone mass in ovariectomized rats.  Endocrinology. 1994;  135 2001-5
• 10 Buelke-Sam J, Bryant H U, Francis P C. The selective estrogen receptor modulator, raloxifene: an overview of nonclinical pharmacology and reproductive and developmental testing. Reprod.  Toxicol.. 1998;  12 217-21
• 11 Smith C L, Nawaz Z, O’Malley B W. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed anti-estrogen, 4-hydroxytamoxifen. Mol.  Endocrinol.. 1997;  11 657-66
• 12 Knauthe R, Diel P, Hegele-Hartung C, Engelhaupt A, Fritzemeier K H. Sexual dimorphism of steroid hormone receptor messenger ribonucleic acid expression and hormonal regulation in rat vascular tissue.  Endocrinology. 1996;  137 3220-7
• 13 Savouret J F, Bailly A, Misrahi M, Rauch C, Redeuilh G, Chauchereau A, Milgrom E. Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene.  EMBO J.. 1991;  10 1875-83
• 14 Diel P, Smolnikar K, Michna H. The pure anti-estrogen ICI 182780 is more effective in the induction of apoptosis and downregulation of BCL-2 than tamoxifen in MCF-7 cells. Breast Cancer Res.  Treat.. 1999;  58 87-97
• 15 Pink J J, Jordan V C. Models of estrogen receptor regulation by estrogens and anti-estrogens in breast cancer cell lines.  Cancer Res.. 1996;  56 2321-30
• 16 Dauvois S, Danielian P S, White R, Parker M G. Anti-estrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc. Natl. Acad. Sci.  USA. 1992;  89 4037-41
• 17 Kuiper G G, Lemmen J G, Carlsson B, Corton J C, Safe S H, van der Saag P T, van der Burg B, Gustafsson J A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.  Endocrinology. 1998;  139 4252-63
• 18 Read L D, Snider C E, Miller J S, Greene G L, Katzenellenbogen B S. Ligand-modulated regulation of progesterone receptor messenger ribonucleic acid and protein in human breast cancer cell lines. Mol.  Endocrinol.. 1988;  2 263-71
• 19 Miodini P, Fioravanti L, Di Fronzo G, Cappelletti V. The two phyto-oestrogens genistein and quercetin exert different effects on oestrogen receptor function. Br. J.  Cancer. 1999;  80 1150-5
• 20 Diel P, Smolnikar K, Michna H. In vitro test systems for the evaluation of the estrogenic activity of natural products.  Planta Medica. 1999;  65 197-203
• 21 Fioravanti L, Cappelletti V, Miodini P, Ronchi E, Brivio M, Di Fronzo G. Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro.  Cancer Lett.. 1998;  130 143-5