Steroid coactivator GRIP-1 regulation with genistein in the rat mammary gland

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Genistein is the predominant isoflavone found in soy and has been shown to suppress the development of chemically-induced mammary cancer in rats. One mechanism through which genistein may exert this chemoprotective effect is via the estrogen receptors-alpha and/or -beta. Nuclear receptors are known to interact with nuclear receptor coactivators, especially the SRC family (SRC-1, GRIP-1, and AIB1), to increase the efficiency of transcriptional regulation. The current study investigates the relationship between dietary genistein consumption and GRIP-1. Female Sprague-Dawley CD rats were fed 250 mg genistein/kg AIN-76A diet or AIN-76A alone from conception until either day 21 or day 50 postpartum. Western blot analysis was performed on the mammary glands of these female rats. There was a 2 fold increase in the level of GRIP-1 protein in the 21 day old mammary gland of animals that were treated with dietary genistein compared to the 21 day old females consuming only AIN 76A. Conversely, the animals treated with dietary genistein until 50 days showed a ∼4 fold decrease in the levels of GRIP-1, when compared to the animals on the AIN-76A diet. We hypothesize that prepubertal exposure to genistein increases cell differentiation and maturation of the mammary gland resulting in protection against mammary cancer. An up-regulation of GRIP-1 due to genistein early in life could interact with nuclear receptors, especially ER, enhancing activation and increasing transcriptional rate at target genes, thus furthering an ER-based mechanism of action for genistein’s protective effect against breast cancer. Subsequently, the adult rat which is characterized as having a more differentiated mammary gland has lower GRIP-1 levels and reduced susceptibility for carcinogenesis. Understanding the mechanism of action of genistein during critical periods of life should allow us to development novel approaches to cancer prevention.