The risk of Alzheimer's disease (AD) is higher in women than in men, a sex difference that likely results from the effects of sex steroid hormones. To investigate this relationship, we first compared progression of β-amyloid (Aβ) pathology in male and female triple transgenic (3xTg-AD) mice. We found that female 3xTg-AD mice exhibit significantly greater Aβ burden and larger behavioral deficits than age-matched males. Next, we evaluated how the organizational effects of sex steroid hormones during postnatal development may affect adult vulnerability to Aβ pathology. We observed that male 3xTg-AD mice demasculinized during early development exhibit significantly increased Aβ accumulation in adulthood. In contrast, female mice defeminized during early development exhibit a more male-like pattern of Aβ pathology in adulthood. Taken together, these results demonstrate significant sex differences in pathology in 3xTg-AD mice and suggest that these differences may be mediated by organizational actions of sex steroid hormones during development.

Prostate cancers (PCas) become resistant to hormone withdrawal through increased androgen receptor (AR) signaling. Here we show increased AR-mediated transcription efficiency in PCa cells that have acquired the ability to grow in low concentrations of androgen. Compared to androgen-dependent PCa cells, these cells showed increased activity of transiently transfected reporters and increased mRNA synthesis relative to levels of AR occupancy of the prostate-specific antigen (PSA) gene. The locus also displayed up to 10-fold-higher levels of histone H3-K9/K14 acetylation and H3-K4 methylation across the entire body of the gene. Although similar increased mRNA expression and locus-wide histone acetylation were also observed at another kallikrein locus (KLK2), at a third AR target locus (TMPRSS2) increased gene expression and locus-wide histone acetylation were not seen in the absence of ligand. Androgen-independent PCa cells have thus evolved three distinctive alterations in AR-mediated transcription. First, increased RNA polymerase initiation and processivity contributed to increased gene expression. Second, AR signaling was more sensitive to ligand. Third, locus-wide chromatin remodeling conducive to the increased gene expression in the absence of ligand was apparent and depended on sustained AR activity. Therefore, increased AR ligand sensitivity as well as locus-specific chromatin alterations contribute to basal gene expression of a subpopulation of specific AR target genes in androgen-independent PCa cells. These features contribute to the androgen-independent phenotype of these cells.The molecular processes that mediate transcription orchestrate cell proliferation, differentiation, and disease progression. Central to this regulation is the dynamic organization and modification of nucleosomes, the basic repeating unit of chromatin that is comprised of 146 bp of DNA wrapped around histone octamers. Accessibility to transcription factors and activation of genes largely depend on diverse posttranslational modifications of amino termini (36, 47) and the more recently implicated globular domains of histones (6). These modifications include acetylation, phosphorylation, and methylation, which covalently add acetyl, phospho, and methyl groups, respectively, to specific residues of core histones. The well-characterized acetylation and methylation of lysines in histones H3 and H4 are highly correlated with transcriptional activation. Acetylation, catalyzed by histone acetyltransferases such as p300/CBP, is reversed by the activity of histone deacetylases, which mediate transcriptional repression (21). Methylation at histone H3 (K4) is catalyzed by specific methyltransferases often found in large complexes such as ALL-1 (32). This process is reversed by the action of a recently identified lysinespecific histone demethylase, LSD1 (39, 40). The complex interactions between the different histone tail modifications have led to the "histone code hypothesis," which suggests that specific histone modifications affect and interac...

This study does not support the hypothesis that the ratio of the two hydroxylated metabolites (2-OHE1/16alpha-OHE1) is an important risk factor for breast cancer.

Background Based on the hypothesized protective effect, we examined the effect of soy foods on estrogens in nipple aspirate fluid (NAF) and serum, possible indicators of breast cancer risk. Methods In a cross-over design, we randomized 96 women who produced ≥10 μL NAF to a high- or low-soy diet for 6-months. During the high-soy diet, participants consumed 2 soy servings of soy milk, tofu, or soy nuts (approximately 50 mg of isoflavones/day); during the low-soy diet, they maintained their usual diet. Six NAF samples were obtained using a FirstCyte© Aspirator. Estradiol (E2) and estrone sulfate (E1S) were assessed in NAF and estrone (E1) in serum only using highly sensitive radioimmunoassays. Mixed-effects regression models accounting for repeated measures and left-censoring limits were applied. Results Mean E2 and E1S were lower during the high-soy than the low-soy diet (113 vs. 313 pg/mL and 46 vs. 68 ng/mL, respectively) without reaching significance (p=0.07); the interaction between group and diet and was not significant. There was no effect of the soy treatment on serum E2 (p=0.76), E1 (p=0.86), or E1S (p=0.56). Within individuals, NAF and serum levels of E2 (rs=0.37; p<0.001) but not E1S (rs=0.004; p=0.97) were correlated. E2 and E1S in NAF and serum were strongly associated (rs=0.78 and rs=0.48; p<0.001). Conclusions Soy foods in amounts consumed by Asians did not significantly modify estrogen levels in NAF and serum. Impact The trend towards lower estrogens in NAF during the high-soy diet counters concerns about adverse effects of soy foods on breast cancer risk.