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Genistein Enhances Insulin-Like Growth Factor Signaling Pathway in Human Breast Cancer (MCF-7) Cells

Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis (W.-F.C., M.-S.W.), Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region, People’s Republic of China; and Department of Physiology (W.-F.C.), Medical College of Qingdao University, Qingdao 266021, People’s Republic of China

Address all correspondence and requests for reprints to: Dr. Man-Sau Wong, Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region, People’s Republic of China. E-mail: bcmswong{at}polyu.edu.hk.

Physiological concentration of genistein, a natural isoflavonoid phytoestrogen, stimulates human breast cancer (MCF-7) cells proliferation. In this study, we hypothesize that low concentration of genistein mimics the action of 17ß-estradiol in stimulation of MCF-7 cell growth by enhancement of IGF-I signaling pathway. Genistein, at 1 µM, stimulated the growth of MCF-7 cells. Cell cycle analysis showed that 1 µM genistein significantly increased the S phase and decreased the G0G1 phase of MCF-7 cells. The protein and mRNA expression of IGF-I receptor (IGF-IR) and insulin receptor substrate (IRS)-1, but not Src homology/collagen protein, increased in response to 1 µM genistein in a time-dependent manner. These effects could be completely abolished by cotreatment of MCF-7 cells with estrogen antagonist ICI 182,780 (1 µM) and tamoxifen (0.1 µM). Our results also showed that genistein induction of IGF-IR and IRS-1 expression resulted in enhanced tyrosine phosphorylation of IGF-IR and IRS-1 on IGF-I stimulation. Taken together, these data provide the first evidence that the IGF-IR pathway is involved in the proliferative effect of low-dose genistein in MCF-7 cells.

This work was supported by the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (AOE/P-10/01), the Area of Strategic Development Grant of the Hong Kong Polytechnic University (A014), and the Central Allocation Grant from the Research Committee of the Hong Kong Polytechnic University (G-W105, G-YC81).

Abbreviations: AF, Activation function(s); E₂, 17-ß-estradiol; ER, estrogen receptor(s); FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IGF-IR, IGF-I receptor; IRS-1, insulin receptor substrate 1; MTT, 3-[4, 5-dimethylthiazol 2-yl]-2, 5-diphenyltetrazolium bromide; Shc, Src homology/collagen; TAM, tamoxifen.

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