BRCA1 and p53 regulate critical prostate cancer pathways.

BACKGROUND: Loss or mutations of the BRCA1 gene are associated with increased risk of breast and ovarian cancers and with prostate cancer (PCa) aggressiveness. Previously, we identified GADD153 as a target of BRCA1 protein, which increases doxorubicin sensitivity in human p53 -/- PCa cells (PC3). Considering that p53 is a crucial target in cancer therapy, in this work we investigated p53 role in the regulation of transcription of GADD153. METHODS: We performed reverse transcription quantitative PCR (RT-qPCR), western blot and luciferase assays to analyze GADD153 and/or BRCA1 expression in response to ultraviolet or doxorubicin exposure in PC3 p53 stable-transfected cells and LNCaP (p53+/+) cells. BRCA1 protein recruitment to GADD153 promoter was studied by chromatin immunoprecipitation-qPCR. To assess expression of BRCA1 and/or p53 target genes, we used a panel of stable-transfected PCa cell lines. We finally analyzed these genes in vivo using BRCA1-depleted PCa xenograft models. RESULTS: We found that GADD153 was highly induced by doxorubicin in PC3 cells; however, this response was totally abolished in LNCaP (p53wt) and in p53-restituted PC3 cells. Furthermore, BRCA1 protein associates to GADD153 promoter after DNA damage in the presence of p53. Additionally, we demonstrated that BRCA1 and/or p53 modulate genes involved in DNA damage and cell cycle regulation (cyclin D1, BLM, BRCA2, DDB2, p21(WAF1/CIP1), H3F3B, GADD153, GADD45A, FEN1, CCNB2), EMT (E-cadherin, ß-catenin, vimentin, fibronectin, slug, snail) and Hedgehog pathways (SHH, IHH, DHH, Gli1, PATCH1). Furthermore, xenograft studies demonstrated that BRCA1 knockdown in PC3 cells increased tumor growth and modulated these genes in vivo. CONCLUSIONS: Although BRCA1 induces GADD153 in a p53 independent manner, p53 abolished GADD153 induction in response to DNA damage. In addition, several important PCa targets are modulated by BRCA1 and p53. Altogether, these data might be important to understand the therapy response of PCa patients.

Prevalence of overweight, obesity and underweight among 5-year-old children in Saint Lucia by three methods of classification and a comparison with historical rates.

BACKGROUND: The study aimed to determine if child obesity rates have risen in the Caribbean nation of Saint Lucia, as found globally, and whether under-nutrition coexists, as in other developing nations. The average adult in Saint Lucia is overweight, thus considerable child obesity might be expected, but there are no current data. METHODS: Heights and weights were obtained from a sample (n= 425) of the 2001 birth cohort of Saint Lucian children measured during the nation-wide 2006/2007 Prior to School Entry Five-Year Assessment. Prevalence of overweight, obesity and underweight were estimated by Centers for Disease Control (CDC), Cole et al. and new World Health Organization (WHO) methods. Previously reported 1976 estimates, including children ≤60 months of age only, based on National Centre for Health Statistics curves, were adjusted to new WHO equivalents using an algorithm developed by Yang and de Onis, and compared with rates in our subsample of children ≤60 months of age (n= 99). RESULTS: Regardless of classification method, overweight and obesity rates were high: 14.4% and 9.2% (WHO); 11.3% and 12.0% (CDC); and 9.9% and 7.1% (Cole et al.), respectively. Underweight estimates also varied: 4.7% (WHO); 11.3% (CDC) and 6.6% (Cole et al.). Obesity in our young subsample (15.2%; WHO) was more than 3 times the adjusted 1976 rate (4.3%). CONCLUSIONS: Obesity among Saint Lucian pre-schoolers has tripled in 30 years. Our findings also suggest that this country, like many undergoing a 'nutrition transition', faces the dual challenge of over-nutrition and under-nutrition. Routine monitoring of overweight and underweight is needed in Saint Lucia, as is the implementation and evaluation of programmes to address these problems.