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Tumor-promoting effects of genistein and estrogen receptor beta in prostate cancer Nakamura, Hisae

Abstract

Genistein is an isoflavone found in soy, and its chemotherapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. Using patient-derived prostate cancer xenograft models, in which clinical prostatectomy samples were grafted into immune deficient mice, this study showed that genistein promoted metastatic progression in vivo. To test if the metatstasis-promoting effects of genistein may be mediated via ERβ activation, we treated the xenografted mice with genistein, an anti-estrogen compound (i.e. ICI 182 780) or a combination of both. The results showed that anti-estrogen treatment significantly decreased metastatic spread compared to genistein, which promoted lung metastasis in a dose-dependent manner. Gene expression analyses showed that genistein and anti-estrogen treatments targeted the same signaling pathway but different molecules, producing opposite effects on tumour biology. Genistein stimulated expression of upstream molecules that reside in the Focal Adhesion Kinase (FAK) pathway, while anti-estrogen down-regulated downstream molecules within the same pathway. Further analysis of the microarray data revealed a unique set of genes that were up-regulated by genistein and also were down-regulated by ICI 182,780. Five out of the six genes identified from this comparison belonged to the metallothionein (MT) gene family. Using qRT-PCR, the changes in expression levels were validated in metastatic and non-metastatic tumour lines of LTL313b, both of which had been derived from the same PCa patient, indicating a strong association between MT gene expression and prostate cancer metastasis. In summary, genistein-activated-ERβ promotes metastasis in two ways; genomic and non-genomic pathways. In the non-genomic pathway, ERβ stimulates kinase signaling pathways, leading to cell survival and increased motility. In the genomic pathway, ERβ increases MT and/or other metastasis-associated gene expression, which can be inhibited by anti-estrogen treatment. This study has demonstrated that genistein elicits cancer promoting effects in vivo and that ERβ is important in metastatic progression of human PCa. The significant inhibition of metastasis by anti-estrogen treatment shown here potentiates a promising new selective estrogen receptor modulator treatment for metastatic patients.

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