ABSTRACT
Cancer-associated fibroblasts (CAFs), the most abundant and probably the most active cellular component of breast cancer-associated stroma, promote carcinogenesis through paracrine effects; however, the molecular basis remains elusive. We have shown here that p16(INK4A) expression is reduced in 83% CAFs as compared with their normal adjacent counterparts cancer-free tissues isolated from the same patients. This decrease is mainly due to AUF1-dependent higher turnover of the CDKN2A mRNA in CAFs. Importantly, p16(INK4A) downregulation using specific siRNA activated breast fibroblasts and increased the expression/secretion levels of stromal cell-derived factor 1 (SDF-1) and matrix metalloproteinase (MMP)-2. Consequently, media conditioned with these cells stimulated the proliferation of epithelial cells. Furthermore, the migration/invasion of breast cancer cells was also enhanced in an SDF-1-dependent manner. This effect was mediated through inducing an epithelial-mesenchymal transition state. By contrast, increase in p16(INK4A) level through ectopic expression or AUF1 downregulation, reduced the secreted levels of SDF-1 and MMP-2 and suppressed the pro-carcinogenic effects of CAFs. In addition, p16(INK4A)-defective fibroblasts accelerated breast tumor xenograft formation and growth rate in mice. Importantly, tumors formed in the presence of p16(INK4A)-defective fibroblasts exhibited higher levels of active Akt, Cox-2, MMP-2 and MMP-9, showing their greater aggressiveness as compared with xenografts formed in the presence of p16(INK4A)-proficient fibroblasts. These results provide the first indication that p16(INK4A) downregulation in breast stromal fibroblasts is an important step toward their activation.
Subject(s)
Breast Neoplasms/pathology , Breast/pathology , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Fibroblasts/pathology , Stromal Cells/pathology , Actins/genetics , Actins/metabolism , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Movement/genetics , Chemokine CXCL12/genetics , Chemokine CXCL12/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Down-Regulation , Epithelial-Mesenchymal Transition , Female , Fibroblasts/metabolism , Gene Expression Regulation , Heterogeneous Nuclear Ribonucleoprotein D0 , Heterogeneous-Nuclear Ribonucleoprotein D/genetics , Humans , Matrix Metalloproteinase 2/genetics , Mice , RNA, Messenger/metabolism , RNA, Small Interfering , Stromal Cells/cytology , Stromal Cells/metabolism , Xenograft Model Antitumor AssaysABSTRACT
PRIMARY OBJECTIVE: To determine anthropometric measurements of adolescent Bahraini girls, including obesity and fat composition. METHODS AND PROCEDURES: A cross-sectional sample of 584 Bahraini girls aged 12-19 years, were selected from schools using multistage stratified sampling procedure. Fifteen anthropometric measurements were taken (weight, height, circumferences for upper arm, upper forearm, upper chest, chest, waist, hip, thigh and medial calf, triceps, biceps, subscapular and suprailiac). Body mass index (BMI), waist/hip ratio, sum of skinfold thickness and % body fat were also computed. MAIN OUTCOMES AND RESULTS: The findings revealed a significant increase in all anthropometric measurements with increase in age. The mean weights for girls was higher than those reported in 1986 for the same age group, but no difference was observed in the mean heights, indicating a trend toward overweight. Using the 85th and 95th centiles of the National Health and Nutrition Examination Survey I (NHANESI) BMI distribution to define respectively overweight and obesity, the prevalence of overweight was 38.5% and of obesity was 6.3%. The means for BMI, waist/hip ratio, sum of skinfold thickness and % body fat were higher than those reported in many developed and developing countries. CONCLUSIONS: Bahraini adolescent girls have a higher proportion of body fat than their counterparts in many Western countries. This may contribute to some chronic diseases in adulthood. An intervention programme, therefore, is urgently needed to reduce overweight and obesity at childhood and adolescent stages.
Subject(s)
Adipose Tissue , Body Composition , Obesity/epidemiology , Adolescent , Adult , Anthropometry , Bahrain/epidemiology , Cross-Sectional Studies , Female , HumansABSTRACT
A sample of 420 women who attended a physical fitness program run by General Organization for Youth and Sport, was selected to study the association between obesity and some factors among adult females in Bahrain. Women were grouped into two categories, obese and non-obese, based on Body Mass Index (wt/ht2). The results revealed that age, education, employment, marital status, family size and practicing exercises before joining the fitness program have a statistically significant association with obesity, while ownership of cars, availability of housemaids, family history of obesity and meal patterns have no statistically significant association. There were no differences in source of nutrition information between obese and non-obese women. The study suggested that health education programs should focus on both sociocultural factors and health factors for preventing obesity in the community.
