Glucocorticoid receptor (GR) exerts anti-inflammatory action in part by antagonizing proinflammatory transcription factors such as the nuclear factor kappa-b (NFKB). Here, we assess the crosstalk of activated GR and RELA (p65, major NFKB component) by global identification of their binding sites and target genes. We show that coactivation of GR and p65 alters the repertoire of regulated genes and results in their association with novel sites in a mutually dependent manner. These novel sites predominantly cluster with p65 target genes that are antagonized by activated GR and vice versa. Our data show that coactivation of GR and NFKB alters signaling pathways that are regulated by each factor separately and provide insight into the networks underlying the GR and NFKB crosstalk.

Introduction: Mucin 1 (MUC1) is a high molecular weight glycoprotein overexpressed on adenocarcinoma cells and is a target for immunotherapy protocols. To date, clinical trials against MUC1 have included advanced cancer patients. Herein, we report a trial using early stage breast cancer patients and injection of oxidized mannan-MUC1. Method: In a randomized, double-blind study, 31 patients with stage II breast cancer and with no evidence of disease received subcutaneous injections of either placebo or oxidized mannan-MUC1, to immunize against MUC1 and prevent cancer reoccurrence/metastases. Twenty-eight patients received the full course of injections of either oxidized mannan-MUC1 or placebo. Survival and immunological assays were assessed. Results: After more than 5.5 years had elapsed since the last patient began treatment (8.5 years from the start of treatment of the first patient), the recurrence rate in patients receiving the placebo was 27% (4/15; the expected rate of recurrence in stage II breast cancer); those receiving immunotherapy had no recurrences (0/16), and this finding was statistically significant (P = 0.0292). Of the patients receiving oxidized mannan-MUC1, nine out of 13 had measurable antibodies to MUC1 and four out of 10 had MUC1-specific T cell responses; none of the placebo-treated patients exhibited an immune response to MUC1. Conclusion: The results suggest that, in early breast cancer, MUC1 immunotherapy is beneficial, and that a larger phase III study should be undertaken.

Bisphenol A (BPA) is an estrogen-mimicking endocrine disruptor. Early-life exposures to low doses of BPA exert long-lasting effects on animals' reproductive and brain physiology. However, little is known about the effects of BPA on the stress–response system. Given the interaction of sex and stress hormones, we examined the effect of a low perinatal BPA exposure on the function of the hypothalamic–pituitary–adrenal (HPA) axis at rest and upon application of acute stress. Throughout pregnancy and lactation rats received daily 40 μg BPA/kg body weight orally via cornflakes. We studied the effect of this low but chronic exposure to BPA in the male and female offspring at puberty. BPA exposure led to abnormal adrenal histology including reduced zona reticularis especially in male offspring, hyperplasia of zona fasciculata in both sexes, and increased adrenal weight in female offspring. BPA-treated females had increased basal corticosterone and reduced hypothalamic glucocorticoid receptors (GR) levels. Stressed BPA-exposed females exhibited anxiety-like behavioral coping, a less rigorous corticosterone response, and did not downregulate GR in the hypothalamus, compared with control females. BPA-exposed males exhibited a heightened corticosterone stress response compared with females; they also displayed increased pro-opiomelanocortin mRNA levels and retained the prestress levels of pituitary corticotropin-releasing hormone-receptor 1, compared with control males. We found that perinatal chronic exposure to a low dose of BPA perturbs the basal and stress-induced activity of the HPA axis in a sexually dimorphic manner at adolescence. Exposure to BPA might contribute to increased susceptibility to stress-related disorders in later life.