Stress exposure has been proposed to contribute to the etiology of breast cancer. However, the validity of this assertion and the possible mechanisms involved are not well established. Epidemiologic studies differ in their assessment of the relative contribution of stress to breast cancer risk, while physiological studies propose a clear connection but lack the knowledge of intracellular pathways involved. The present review aims to consolidate the findings from different fields of research (including epidemiology, physiology, and molecular biology) in order to present a comprehensive picture of what we know to date about the role of stress in breast cancer development.

Psychological stress has been correlated with breast cancer development in numerous epidemiological studies. However, physiological and molecular models which may account for this association are not readily available. We have found that the stress hormone hydrocortisone (cortisol) down-regulates the expression of the breast cancer susceptibility gene BRCA1 in the nonmalignant mouse mammary cell line EPH4. This effect is concentration-dependent, is reliant on the continuous presence of hydrocortisone, and is not affected by the addition of lactogenic hormones, or growth conditions. Hydrocortisone was also found to negate a known positive effect of estrogen on BRCA1 expression and, therefore, may interfere with estrogen-related signaling in mammary epithelial cells. The repressive effect of hydrocortisone is diminished or lost in the mouse mammary lines HC-11 and SP1, respectively, suggesting regulation of the BRCA1 may differ between lines. We have uncovered two promoter regulatory sites, which are involved in BRCA1 regulation by hydrocortisone, namely the RIBS and UP regulatory elements. Binding of the transcription factor GABP to both sites is lost upon hydrocortisone addition, though the levels of these factors are not altered by hydrocortisone treatment. Because BRCA1 activity is important for a number of intracellular pathways involved in prevention of tumorigenesis, its observed down-regulation may represent a novel molecular mechanism for cortisol's involvement in breast cancer development.

Loss of BRCA1 tumor suppressor function is a critical event in breast tumorigenesis. We have previously identified the stress hormone hydrocortisone as a negative regulator of BRCA1 expression in nonmalignant mammary cells. Here, we have identified a direct role for the unliganded glucocorticoid receptor (GR) in BRCA1 upregulation in the absence of hydrocortisone. The positive regulatory effect of GR is lost upon the addition of hydrocortisone. We have shown that GR interacts with the BRCA1 promoter only in the absence of hydrocortisone, and that this interaction is mediated through the b-subunit of the ets transcription factor GA-binding protein (GABP) at the RIBS promoter element. GR and GABPb interact in both coimmunoprecipitation and mammalian two-hybrid assays, and this interaction involves the N-terminal to central regions of both proteins. This work presents the first evidence of a ligand-independent role for GR as a positive regulator of gene expression, and loss of GR from the BRCA1 promoter in response to stress hormones leads to decreased BRCA1 expression. Because low levels of BRCA1 have been implicated in the development of sporadic breast cancer, this may represent a novel mechanism through which prolonged stress signaling increases breast cancer risk. Mol Cancer Res; 10(4); 558-69. Ó2012 AACR. IntroductionGerm line mutations in the BRCA1 tumor suppressor contribute to familial breast tumor formation but BRCA1 mutations do not seem to occur in sporadic breast cancer tumors (1). Instead, sporadic breast tumors exhibit decreased levels of BRCA1 expression, and the degree of downregulation seems to be correlated with tumor grade, rate of tumor progression, and risk of metastasis (2-6). This implies that loss of BRCA1 function, either through decreased activity or downregulation of expression, is a critical event in the etiology of breast cancer. Phenotypically normal breast epithelial cells from individuals harboring a BRCA1 germ line mutation (a so called "one-hit" mutation accompanied by a 50% decrease in BRCA1 function) express an altered mRNA profile compared with normal cells from individuals without a BRCA1 mutation (7). This suggests that decreases in functional BRCA1

Background Colonoscopy remains the gold standard for the investigation of abnormalities within the colon. However, its success is highly dependent on the quality of bowel preparation. The objective of this study was to compare the bowel preparation efficacy of picosulfate/magnesium citrate (PMC) vs polyethylene glycol (PEG) in a one-day vs two-day split dose regimen. Methods A prospective, randomized, controlled trial was conducted at the Forzani & MacPhail Colon Cancer Screening Centre in Calgary, Canada. 171 colonoscopy outpatients were randomized to split-dose PMC or PEG lavage as well as into one-day split or two-day split regimens in blocks of eight. Bowel preparation quality was recorded in a blinded manner by the endoscopist using the Ottawa Bowel Preparation Scale (OBPS) prior to washing or suctioning. The scale results were analyzed using a two-factor analysis of variance. Results 141 patients received complete colonoscopies (PMC-71; PEG-70). PEG was found to be superior to PMC (mean OBPS: 4.14 ± 2.64 vs 5.11 ± 3.44, p = 0.019), when adjusted for administration regimen, leading to significantly more adequate bowel preparations (79.7% vs 59.7%, p = 0.007). A two-day split dose was superior to a one-day split dose regimen (mean OBPS: 3.68± 2.82 vs 5.69 ± 3.06, p<0.001). Two-day split dosing also resulted in a better right colon cleanliness score (right bowel OBPS 1.27±0.11 vs 2.10±0.12 for one-day split, P<0.001). Conclusions Optimal bowel preparation was achieved with the use of PEG lavage when administered in a two-day split dose regimen. This trial is registered with ClinicalTrials.gov under identifier NCT01415687.