Molecular actions of phytoestrogens in human breast cancer MCF-7 cells and osteoblastic SaOS-2 cells

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Molecular actions of phytoestrogens in human breast cancer MCF-7 cells and osteoblastic SaOS-2 cells


Author: Chen, Wenfang
Title: Molecular actions of phytoestrogens in human breast cancer MCF-7 cells and osteoblastic SaOS-2 cells
Degree: Ph.D.
Year: 2004
Subject: Hong Kong Polytechnic University -- Dissertations
Soy proteins
Breast -- Cancer
Department: Dept. of Applied Biology and Chemical Technology
Pages: xxv, 287 leaves : ill. (some col.) ; 30 cm
Language: English
InnoPac Record:
Abstract: Estrogens are among the most ubiquitous and important hormones in the female body. After menopause, estradiol levels drop significantly. The goals of estrogen replacement therapy (ERT)/hormone replacement therapy (HRT) are to replace estrogen in a manner that alleviates menopausal symptoms. However, women are reluctant to use ERT/HRT mainly due to the undesirable side-effects. Postmenopausal women are more inclined to use natural remedies. Of all the natural alternatives, phytoestrogens appear to offer the greatest potential. Among all the major phytoestrogens, isoflavones genistein and ginsenoside Rgl are selected in our study for investigation of molecular actions in breast cancer and bone cells. Genistein is the most extensively studied phytoestrogen where their biological activities are reported by many studies, while ginsenoside Rgl is a newly identified phytoestrogen from ginseng root. The study of their molecular actions will provide useful insight for their potential applications as alternative to HRT. In the present study, two in vitro cell model systems, human breast cancer MCF-7 cell and human osteoblastic SaOS-2 cell, were used for studying the mechanism of action of the two selected phytoestrogens. Biphasic effects of genistein have been demonstrated on the growth of ER positive human breast cancer MCF-7 cells. In the absence of endogenous estrogens, physiological concentrations of genistein stimulate the cell growth, whereas high concentrations of genistein have inhibitory effect. Using cDNA microarray technology, genes differentially regulated by high concentrations of genistein were identified. In particular, as confirmed by RT-PCR, genistein up-regulated heat shock protein 105 mRNA and down-regulated mRNA expression of serum response factor, estrogen receptor 帢, disabled homolog 2 and recombination activation gene 1. These results suggest that the inhibitory action of genistein on human breast cancer cells appears to be complex and is only partially mediated by the alteration of ER-dependent pathway. In this cell model system our results also indicated both genistein (1uM) and Rgl (1pM) mimic the action of estradiol in stimulation of MCF-7 cell growth by inducing IGF-LR and IRS-1 expression. The increase in expression of these key proteins in MCF-7 cells by genistein and Rgl were ER dependent and accompanied by an enhancement of IGF-I mediated signaling. Thus, caution is warranted for the consumption of soy products containing genistein or ginseng products amongst pre- and post-menopausal women who suffered from ER-positive breast cancer. In human osteoblastic SaOS-2 cell model system, we attempted to investigate if genistein and Rgl have anabolic effects on osteoblastic cells. Our results showed that genistein could induce ALP activity and OPG expression in a dose-dependent manner. Genistein or estrogen pretreatment significantly attenuated PTH-induced decrease in OPG expression and increase in RANKL expression. Pretreatment with genistein or estrogen also has additive effects on PTH-induced ALP activity. However there is no significant effect of Rgl on osteoblastic SaOS-2 cells, suggesting not all phytoestrogen can have anabolic effect on bone. These results help to elucidate the detailed mechanism of phytoestrogens on different cell types and provide information to assess the potential risk and benefit of phytoestrogens consumption in postmenopausal women.

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