ABSTRACT
BRCA1 (breast-cancer susceptibility gene 1) is a tumour suppressor gene that is mutated in the germline of women with a genetic predisposition to breast and ovarian cancer. In this review, we examine the role played by BRCA1 in mediating the cellular response to stress. We review the role played by BRCA1 in detecting and signalling the presence of DNA damage, particularly double-strand DNA breaks, and look at the evidence to support a role for BRCA1 in regulating stress response pathways such as the c-Jun N-terminal kinase/stress-activated protein kinase pathway. In addition, we examine the role played by BRCA1 in mediating both cell-cycle arrest and apoptosis following different types of cellular insult, and how this may be modulated by the presence or absence of associated proteins such as p53. Finally, we explore the possibility that many of the functions associated with BRCA1 may be based on transcriptional regulation of key downstream genes that have been implicated in the regulation of these specific cellular pathways.
Subject(s)
BRCA1 Protein/physiology , DNA Damage , DNA Repair , Genes, BRCA1 , Transcription, Genetic , Animals , Apoptosis , Blotting, Northern , Cell Cycle , G2 Phase , Humans , Interferon-gamma/metabolism , JNK Mitogen-Activated Protein Kinases , Mitogen-Activated Protein Kinases/metabolism , Mitosis , Paclitaxel/pharmacology , Stress, Physiological , Time Factors , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolism , Ultraviolet RaysABSTRACT
Our previous studies have shown that social housing conditions can significantly alter the growth rate of the Shionogi mouse mammary carcinoma (SC115). The present study extended our investigations to the molecular level by examining stressor effects on the expression of a group of stress-responsive proteins, the heat shock proteins (HSPs). We hypothesized that HSP expression in SC115 cells may be altered by (a) different social housing conditions in vivo and (b) steroid hormone and growth factor exposure in vitro. Mice were reared in groups (G) or as individuals (I). Immediately following tumor cell injection, mice were rehoused from group to individual (GI), from individual to group (IG), or they remained in groups (GG). Tumor tissue was resected at 0.8 g or 3.0 g, as evidence suggests that tumor size affects HSP expression, which in turn affects proliferation. The data demonstrate that expression of HSP25, 70, and 90 was increased in tumors from mice in the IG compared to GG and GI mice, at both tumor weights examined. In addition, in IG mice, HSP90 expression was greater in 0.8 g compared to 3.0 g tumors. Under controlled culture conditions, hormones known to stimulate SC115 growth both in vivo and in vitro altered HSP expression. Physiological levels of dihydrotestosterone (DHT) and pharmacological levels of hydrocortisone (HC) upregulated expression of HSP25, whereas physiological levels of beta-estradiol (E2) upregulated expression of HSP90. These data are the first to demonstrate that a psychosocial stressor, a change in social housing condition, can induce differential HSP expression. Further, these data show that hormones that regulate SC115 tumor growth, also alter HSP expression.
Subject(s)
Heat-Shock Proteins/metabolism , Housing, Animal , Mammary Neoplasms, Experimental/metabolism , Stress, Physiological/metabolism , Animals , Blotting, Western , Cell Division , Disease Models, Animal , Male , Mammary Neoplasms, Experimental/complications , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred Strains , Stress, Physiological/complications , Tumor Cells, CulturedABSTRACT
Stressful life events and the ability to cope with stress may play a role in the progression of breast cancer; however, the complex relationship between stressors and tumor growth is difficult to investigate in humans. Our studies have utilized the androgen-responsive Shionogi mouse mammary carcinoma (AR SC115) in male mice to investigate the effects of social housing condition on tumor growth rates and responses to chemotherapy. We demonstrate that, depending on social housing condition, mammary tumor growth and response to chemotherapy can both increase and decrease. We have examined the possible role(s) of 1) psychosocial variables, 2) testosterone and corticosterone, hormones altered by stress and known to stimulate SC115 cells in vivo and in vitro, 3) NK cells, one of the body's first lines of defense against tumor cells, 4) stress proteins, in mediating the differential tumor growth rates observed in our model. This review discusses the investigations we have undertaken to elucidate the mechanisms through which a psychosocial stressor, social housing condition, can alter tumor growth rate.
