Cellular homeostasis in higher organisms is maintained by balancing cell growth, differentiation, and death. Two important systems that transmit extracellular signals into the machinery of the cell nucleus are the signaling pathways that activate nuclear factor kappaB (NF-kappaB) and estrogen receptor (ER). These two transcription factors induce expression of genes that control cell fates, including proliferation and cell death (apoptosis). However, ER has anti-inflammatory effects, whereas activated NF-kappaB initiates and maintains cellular inflammatory responses. Recent investigations elucidated a nonclassical and nongenomic effect of ER: inhibition of NF-kappaB activation and the inflammatory response. In breast cancer, antiestrogen therapy might cause reactivation of NF-kappaB, potentially rerouting a proliferative signal to breast cancer cells and contributing to hormone resistance. Thus, ER ligands that selectively block NF-kappaB activation could provide specific potential therapy for hormone-resistant ER-positive breast cancers.
Nuclear factor-KB (NF-KB), a transcription factor with pleotropic effects, is a downstream mediator of growth signaling in estrogen receptor (ER)-negative and erbB family particularly erbB2 (HER-2/neu) receptor -positive cancer. We previously reported activation of NF-KB in ER-negative breast cancer cells and breast tumor specimens, but the consequence of inhibiting NF-KB activation in this subclass of breast cancer has not been shown. In this study, we investigated the role of NF-KB activation by studying the tumorigenic potential of cells expressing genetically manipulated, inducible, dominant-negative inhibitory KB kinase (IKK) B in xenograft tumor model. Conditional inhibition of NF-KB activation by the inducible expression of dominant-negative IKKB simultaneously blocked cell proliferation, reinstated apoptosis, and dramatically blocked xenograft tumor formation. Secondly, the humanized anti-erbB2 antibody trastuzumab (Herceptin) and the specific IKK inhibitor NF-KB essential modifierbinding domain peptide both blocked NF-KB activation and cell proliferation and reinstated apoptosis in two ER-negative and erbB2-positive human breast cancer cell lines that are used as representative model systems.Combinations of these two target-specific inhibitors synergistically blocked cell proliferation at concentrations that were singly ineffective. Inhibition of NF-KB activation with two other low molecular weight compounds, PS1145 and PS341, which inhibited IKK activity and proteasomemediated phosphorylated inhibitory KB protein degradation, respectively, blocked erbB2-mediated cell growth and reversed antiapoptotic machinery. These results implicate NF-KB activation in the tumorigenesis and progression of ER-negative breast cancer. It is postulated that this transcription factor and its activation cascade offer therapeutic targets for erbB2-positive and ER-negative breast cancer. [Mol Cancer Ther 2007;6(7):1973 -82]
A prospective audit of 76 patients undergoing elective orthopaedic surgery was performed. The aim of this audit was to assess how effectively patients are consented at a busy teaching hospital, and to suggest improvements to the process. Evaluates the level of information attained by patients after giving consent and their overall satisfaction with the process by use of a questionnaire. Results demonstrated that patients were often given incomplete information about their management. Despite this, patients themselves felt that the level of information given to them was appropriate, and allowed them to make an informed decision. Suggests the use of written information sheets and Internet Web sites to supplement the provision of information to patients. These modalities will allow patients to access as much information as they desire, while avoiding any potential anxiety due to provision of excess information.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.