Genistein Chemoprevention: Timing and Mechanisms of Action in Murine Mammary and Prostate

Abstract

We investigated the potential of genistein, the primary isoflavone of soy, to protect against breast and prostate cancers in animal models. For mammary cancer studies, Sprague-Dawley rats were fed AIN-76A diet plus minus 250 mg genistein/kg diet. Dimethylbenz[a]anthracene was administered by gavage at d 50 postpartum to induce mammary tumors. Mammary cancer chemoprevention was demonstrated after prepubertal and combined prepubertal and adult genistein treatments but not after prenatal- or adult-only treatments, demonstrating that the timing of exposure to genistein is important for mammary cancer chemoprevention. The cellular mechanism of action was found to be mammary gland and cell differentiation, as shown by whole-mount analysis and beta-casein expression. An imprinting effect was shown for epidermal growth factor receptor expression in mammary terminal end buds. For prostate cancer studies, we used two models. The first was a chemically (N-methylnitrosourea) induced prostate cancer rat model. Genistein in the diet inhibited the development of invasive adenocarcinomas in a dose-dependent manner. The second model was a transgenic mouse model that resulted in spontaneously developing adenocarcinoma tumor of the prostate. Genistein in the diet reduced the incidence of poorly differentiated prostatic adenocarcinomas in a dose-dependent manner and down-regulated androgen receptor, estrogen receptor-alpha, progesterone receptor, epidermal growth factor receptor, insulin-like growth factor-I, and extracellular signal-regulated kinase-1 but not estrogen receptor-beta and transforming growth factor-alpha mRNA expressions. We conclude that dietary genistein protects against mammary and prostate cancers by regulating specific sex steroid receptors and growth factor signaling pathways.

Dietary Determinants of Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Proteins 1, -2 and -3 in Women in the Netherlands

“…tamoxifen, raloxifene) have been shown to decrease circulating IGF-I levels in previous human studies [27][28][29], and may also increase some IGFBP levels [27,28]. Additionally, studies in mouse models showed a reduction of serum IGF-I or IGF-I mRNA expression in breast or prostate tissue by phytoestrogens [52][53][54]. Residual + total energy intake in linear regression model.…”

The role of early life genistein exposures in modifying breast cancer risk

“…The third IF of SPI is glycitin and its aglycone glycitein, but they are present only at low levels. As shown in Table 1, the findings obtained in rats exposed to SPI or purified genistein during the fetal-perinatal period vary from study to study, with three studies reporting an increase in the incidence of either carcinogen-induced tumours (Hilakivi-Clarke et al, 1999;Hilakivi-Clarke et al, 2002) or spontaneous hyperplasias and ductal carcinomas in situ (Foster et al, 2004), one study reporting a reduction in tumour multiplicity and % high grade tumours (Su et al, 2007a), and two studies reporting no effects (Lamartiniere et al, 2002;Pei et al, 2003). Two of these studies investigated the effects on mammary gland morphology in adult rats (Hilakivi-Clarke et al, 2002;Foster et al, 2004).…”

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

“…Since genistein is proposed as a chemoprevention agent for several tumour types (Mentor-Marcel et al, 2001;Lamartiniere et al, 2002), including breast and prostate cancers, we tested its ability to induce BRCA expression. Genistein caused dose-and time-dependent increases in BRCA1 and BRCA2 protein levels in two oestrogen-responsive breast cancer cell lines (MCF-7 and T47D) ( Figure 3D).…”