Molecular basis for estrogen receptor alpha deficiency in BRCA1-linked breast cancer

Background BRCA1-mutant breast tumors are typically estrogen receptor alpha (ER alpha) negative, whereas most sporadic tumors express wild-type BRCA1 and are ER alpha positive. We examined a possible mechanism for the observed ER alpha-negative phenotype of BRCA1-mutant tumors.

Methods We used a breast cancer disease-specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) ( the gene encoding ER alpha), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ER alpha protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA ( siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCA1-specific siRNA. All statistical tests were two-sided.

Results Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors ( 95% confidence interval [CI]=2.6-fold to 40.1-fold, P =.0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ER alpha expression. BRCA1-depleted breast cancer cells expressing exogenous ER alpha were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector ( T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [IC40] for empty vector versus ER alpha: > 10(-5) versus 8.0 x 10(-9) M [ 95% CI=3.1x10(-10) to 3.2 x 10(-6) M]; MCF-7 cells, mean IC40 for empty vector versus ER alpha : > 10(-5) versus 4.9 x 10(-8) M [ 95% CI=2.0 x 10(-9) to 3.9 x 10(-6) M]).

Conclusions BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ER alpha expression.

Effect of osteoporosis on bone mineral density and fracture repair in a rat femoral fracture model

Osteoporosis (OP) is one of the most prevalent bone diseases worldwide with bone fracture the major clinical consequence. The effect of OP on fracture repair is disputed and although it might be expected for fracture repair to be delayed in osteoporotic individuals, a definitive answer to this question still eludes us. The aim of this study was to clarify the effect of osteoporosis in a rodent fracture model. OP was induced in 3-month-old rats (n = 53) by ovariectomy (OVX) followed by an externally fixated, mid-diaphyseal femoral osteotomy at 6 months (OVX group). A further 40 animals underwent a fracture at 6 months (control group). Animals were sacrificed at 1, 2, 4, 6, and 8 weeks postfracture with outcome measures of histology, biomechanical strength testing, pQCT, relative BMD, and motion detection. OVX animals had significantly lower BMD, slower fracture repair (histologically), reduced stiffness in the fractured femora (8 weeks) and strength in the contralateral femora (6 and 8 weeks), increased body weight, and decreased motion. This study has demonstrated that OVX is associated with decrease in BMD (particularly in trabecular bone) and a reduction in the mechanical properties of intact bone and healing fractures. The histological, biomechanical, and radiological measures of union suggest that OVX delayed fracture healing. (C) 2007 Orthopaedic Research Society. Published by Wiley Periodicals.

Ellagic acid, pomegranate and prostate cancer - a mini review.

There is currently a shifting focus towards finding natural compounds that may prevent or treat cancer, due to the problems that exist with current chemotherapeutic regimens. The fruit of the Punica granatum (pomegranate) contains hundreds of phytochemicals and pomegranate extracts have recently been shown to exhibit antioxidant properties, thought to be due to the action of ellagic acid, the main polyphenol in pomegranate. In this mini review the effects of pomegranate extracts and ellagic acid on the proliferation of prostate cancer cells and their future potential are discussed.

Parent-Reported Quality of Life of Children With Cerebral Palsy in Europe

OBJECTIVE. The goal was to determine whether the type and severity of the child's impairments and the family's psychosocial, social, and economic characteristics influence parent-reported child quality of life across the spectrum of severity of cerebral palsy.

METHODS. Our population-based, cross-sectional survey conducted in 2004 to 2005 involved 818 children with cerebral palsy, 8 to 12 years of age, from 7 countries (9 regions) in Europe. Child quality of life was assessed through parent reports by using the Kidscreen questionnaire, and data were analyzed separately for each of its 10 domains.

RESULTS. The parental response rates were >93% for all domains except one. Gross motor function and IQ level were found to be associated independently with quality of life in most domains. However, greater severity of impairment was not always associated with poorer quality of life; in the moods and emotions, self-perception, social acceptance, and school environment domains, less severely impaired children were more likely to have poor quality of life. Pain was associated with poor quality of life in the physical and psychological well-being and self-perception domains. Parents with higher levels of stress were more likely to report poor quality of life in all domains, which suggests that factors other than the severity of the child's impairment may influence the way in which parents report quality of life.

CONCLUSIONS. The parent-reported quality of life for children with cerebral palsy is associated strongly with impairment. However, depending on the areas of life, the most severely impaired children (in terms of motor functioning or intellectual ability) do not always have the poorest quality of life.

Frequency of participation of 8-12 year old children with cerebral palsy: a multi-centre cross sectional European study

Participation in home, school and community is important for all children; and little is known about the frequency of participation of disabled children. Frequency of participation is a valuable outcome measure for evaluating habilitation programmes for disabled children and for planning social and health services.

We investigated how frequency of participation varied between children with cerebral palsy and the general population; and examined variation across countries to understand better how the environmental factors such as legislation, public attitudes and regulation in different countries might influence participation.

We undertook a multi-centre, population-based study in children with and without cerebral palsy. Working from the Life-H instrument, we developed a questionnaire to capture frequency of participation in 8–12-year-old children. In nine regions of seven European countries, parents of 813 children with cerebral palsy and 2939 children from the general populations completed the questionnaire.

Frequency of participation for each question was dichotomised about the median; multivariable logistic regressions were carried out.

In the general population, frequency of participation varied between countries. Children with cerebral palsy participated less frequently in many but not all areas of everyday life, compared with children from the general population. There was regional variation in the domains with reduced participation and in the magnitude of the differences. We discuss how this regional variation might be explained by the different environments in which children live. Attending a special school or class was not associated with further reduction in participation in most areas of everyday life.