At present, surgical intervention is still the standard and most effective treatment for uterine leiomyomas ( Rackow and Arici, 2006 Tulandi, 2007). These tumors represent a tremendous public health burden and economic cost to society. Uterine leiomyomas (i.e., fibroids, myomas) are the leading indication for hysterectomy in the United States with the estimated cumulative incidence of tumors by age 50 being > 80% for black women and nearly 70% for white women in the United States ( Walker and Stewart, 2005 Viswanathan et al., 2007). Taken together, these results suggest that down-regulation of activin A and Smad3, both members of the TGF-ОІ pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Downregulation of TGF-ОІ signaling pathway genes, activin A, activin B, Smad3, TGF-ОІ2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time RT-PCR studies. In this study, using microarray analysis and Ingenuity Pathways Analysisв„ў, we identified genes (up- or down-regulated, в‰Ґ 1.5 fold, P в‰¤ 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 Вµg/ml) in UtLM cells. Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation.

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