PAR Genes: Molecular Probes to Pathological Assessment in Breast Cancer Progression

Taking the issue of tumor categorization a step forward and establish molecular imprints to accompany histopathological assessment is a challenging task. This is important since often patients with similar clinical and pathological tumors may respond differently to a given treatment. Protease-activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR), is the first member of the mammalian PAR family consisting of four genes. PAR1 and PAR2 play a central role in breast cancer. The release of N-terminal peptides during activation and the exposure of a cryptic internal ligand in PARs, endow these receptors with the opportunity to serve as a “mirror-image” index reflecting the level of cell surface PAR1&2-in body fluids. It is possible to use the levels of PAR-released peptide in patients and accordingly determine the choice of treatment. We have both identified PAR1 C-tail as a scaffold site for the immobilization of signaling partners, and the critical minimal binding site. This binding region may be used for future therapeutic modalities in breast cancer, since abrogation of the binding inhibits PAR1 induced breast cancer. Altogether, both PAR1 and PAR2 may serve as molecular probes for breast cancer diagnosis and valuable targets for therapy

Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen

A pivotal role is attributed to the estrogenreceptor (ER) pathway in mediating the effect of estrogen in breast cancer progression. Yet the precise mechanisms of cancer development by estrogen remain poorly understood. Advancing tumor categorization a step forward, and identifying cellular gene fingerprints to accompany histopathological assessment may provide targets for therapy as well as vehicles for evaluating the response to treatment. We report here that in breast carcinoma, estrogen may induce tumor development by eliciting protease-activated receptor-1 (PAR1) gene expression. Induction of PAR1 was shown by electrophoretic mobility shift assay, luciferase reporter gene driven by the hPar1 promoter, and chromatin-immunoprecipitation analyses. Functional estrogen regulation of hPar1 in breast cancer was demonstrated by an endothelial tube-forming network. Notably, tissue-microarray analyses from an established cohort of women diagnosed with invasive breast carcinoma exhibited a significantly shorter disease-free (P 0.006) and overall (P 0.02) survival of patients that were positive for ER and PAR1, compared to ER-positive but PAR1-negative patients. We propose that estrogen transcriptionally regulates hPar1, culminating in an aggressive gene imprint in breast cancer. While ER patients are traditionally treated with hormone therapy, the presence of PAR1 identifies a group of patients that requires additional treatment, such as anti-PAR1 biological vehicles or chemotherapy.—Salah, Z., Uziely, B., Jaber, M., Maoz, M., Cohen, I., Hamburger, T., Maly, B., Peretz, T., B.-S, R. Regulation of human protease-activated receptor 1 (hPar1) gene expression in breast cancer by estrogen

Etk/Bmx Regulates Proteinase-Activated-Receptor1 (PAR1) in Breast Cancer Invasion: Signaling Partners, Hierarchy and Physiological Significance

BACKGROUND: While protease-activated-receptor 1 (PAR(1)) plays a central role in tumor progression, little is known about the cell signaling involved. METHODOLOGY/PRINCIPAL FINDINGS: We show here the impact of PAR(1) cellular activities using both an orthotopic mouse mammary xenograft and a colorectal-liver metastasis model in vivo, with biochemical analyses in vitro. Large and highly vascularized tumors were generated by cells over-expressing wt hPar1, Y397Z hPar1, with persistent signaling, or Y381A hPar1 mutant constructs. In contrast, cells over-expressing the truncated form of hPar1, which lacks the cytoplasmic tail, developed small or no tumors, similar to cells expressing empty vector or control untreated cells. Antibody array membranes revealed essential hPar1 partners including Etk/Bmx and Shc. PAR(1) activation induces Etk/Bmx and Shc binding to the receptor C-tail to form a complex. Y/A mutations in the PAR(1) C-tail did not prevent Shc-PAR(1) association, but enhanced the number of liver metastases compared with the already increased metastases obtained with wt hPar1. We found that Etk/Bmx first binds via the PH domain to a region of seven residues, located between C378-S384 in PAR(1) C-tail, enabling subsequent Shc association. Importantly, expression of the hPar1-7A mutant form (substituted A, residues 378-384), which is incapable of binding Etk/Bmx, resulted in inhibition of invasion through Matrigel-coated membranes. Similarly, knocking down Etk/Bmx inhibited PAR(1)-induced MDA-MB-435 cell migration. In addition, intact spheroid morphogenesis of MCF10A cells is markedly disrupted by the ectopic expression of wt hPar1. In contrast, the forced expression of the hPar1-7A mutant results in normal ball-shaped spheroids. Thus, by preventing binding of Etk/Bmx to PAR(1) -C-tail, hPar1 oncogenic properties are abrogated. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration that a cytoplasmic portion of the PAR(1) C-tail functions as a scaffold site. We identify here essential signaling partners, determine the hierarchy of binding and provide a platform for therapeutic vehicles via definition of the critical PAR(1)-associating region in the breast cancer signaling niche

The oncology nurse coordinator: role perceptions of staff members and nurse coordinators

Abstract Background There is extensive evidence that the role of nurse coordinators is beneficial for patients. Nurse coordinators are more available to patients compared to general registered nurses, know better to control symptoms and work as team players with multiple care providers. Despite its significance, there is a dearth of literature on the subject in Israel and a lack of clarity regarding the definitions of the role in terms of responsibilities and authorities. The aim of the study is to: To examine how the role of nurse oncology coordinator is implemented in various fields of oncology and to describe the actual performance of different kinds of oncology nurse coordinators and staff perceptions regarding this role in one tertiary hospital in Jerusalem. Methods A phenomenological approach was used to explore the participants’ experiences and views of nurse coordinators’ performance. We conducted a qualitative study using in-depth semi-structured interviews. Interviewees included 30 employees from different levels of the hospitals, and leading figures associated with oncology medicine outside of the hospital: Nurses and physicians of the Sharett Oncology Institute of Hadassah Ein Kerem Hospital in Jerusalem, the administrative staff of Hadassah Ein Kerem Hospital, head nurses of the Israel Cancer Association, the chairperson of the Non-Profit Organization of Oncology Nurses, nurse directors at the Ministry of Health Nursing Division, and seven nurse coordinators at Hadassah Ein Kerem Hospital in diverse fields of oncology. Results The nurse coordinator is perceived as an important staff member providing care to cancer patients. Several key elements were found to be common features in the work of all nurse coordinators: emotional support, guidance to patients, and coordination of patients’ care. Conclusions The nurse coordinator plays a noteworthy role in the health care system. In view of the variety of roles that the nurse coordinator assumes in different units, performance standards must be adapted to the performance areas for each unit, as well as nurses’ professional development requirements. Changes in a service organization and careful attention to the continuum of care highlight the need to develop and to strengthen the role of a nurse who coordinates treatment over the entire continuum of care, both in the hospital and in the community

Unemployment Risk and Decreased Income Two and Four Years After Thyroid Cancer Diagnosis: A Population-Based Study

Thyroid cancer (TC) often occurs in relatively young patients and has a high cure rate. However, decreased psychological and physical well-being may reduce the work capability of patients with TC. This study aimed to compare the risk for unemployment and decreased income in TC survivors with a matched non-cancer group at two and four years after diagnosis. The study also aimed to predict unemployment and income changes at two and four years after diagnosis. A historical prospective study design was used, with cohort inception and baseline measurements drawn from the Israeli Central Bureau of Statistics 1995 National Census, with follow-up until 2011. Cancer incidence was obtained from the Israel Cancer Registry, and employment status from the Tax Authority. A matched group was sampled from the census population. Binary logistic regression analyses were used to assess odds ratios (OR) for the study outcomes, controlled for age, sex, ethnicity, education years, socioeconomic position, and employment status at two years before diagnosis. In total, 417 cases of TC and 1277 non-cancer matched subjects were included in the study. People who died during the study period were excluded. The mean age at the time of cancer diagnosis was 43.5 years in the TC group and 43.8 years in the control group (p = 0.6). After adjusting for potential confounders, a positive association was found between TC and risk of unemployment two years after diagnosis (OR = 1.46 [confidence interval (CI) 1.09-1.95]), and decreased income two years after diagnosis (OR = 1.61 [CI 1.23-2.01]) and four years after diagnosis (OR = 1.63 [CI 1.25-2.13]). The association between TC and unemployment at four years after diagnosis weakened and lost significance (OR = 1.30 [CI 0.98-1.72]). TC survivorship was associated with unemployment at two years and decreased income at two and four years after diagnosis. Decreased income may be a marker for a shift to part-time work rather than a return to full-time work. The findings suggest that interventions to enhance the return to full-time work are needed in this populatio

Additional file 2: of The oncology nurse coordinator: role perceptions of staff members and nurse coordinators

Developing and Investigative Items. (DOCX 21 kb

Additional file 1: of The oncology nurse coordinator: role perceptions of staff members and nurse coordinators

Nurse Coordinator: Ministry of Health Job Description. (DOCX 23 kb