Metallothionein 2A expression is associated with cell proliferation in breast cancer

Metallothioneins (MTs) belong to a family of cysteine-rich, metal-binding intracellular proteins, which have been linked with cell proliferation. In this study, expression levels of the 8 known MT-1 and MT-2 functional isoforms in human invasive ductal breast cancer specimens were determined by RT–PCR. The expression profiles of the MT protein and MT-2A mRNA were further evaluated in 79 cases of human invasive ductal breast carcinoma by immunohistochemistry and in situ hybridization, and correlated with cancer cell proliferation (determined by Ki-67 nuclear antigen immunolabeling). MT-1A, MT-1E, MT-1F, MT-1G, MT-1H, MT-1X and MT-2A but not MT-1B, were detected in breast cancer tissue samples. The MT-2A mRNA transcript was the highest among all the isoforms detected. A positive correlation was observed between MT-2A mRNA and MT protein expression with Ki-67 labeling (P = 0.0003 and P < 0.0001, respectively) but not with apoptosis (P = 0.1244 and P = 0.8189, respectively). Co-localization of the MT protein and Ki-67 nuclear antigen in breast cancer cells was demonstrated by double immunofluorescence staining. There was also significantly higher MT protein and MT-2A mRNA expression in histological grade 3 tumors than in histological grade 1 and 2 tumors. The finding that MT 2A appears to be the main isoform associated with cell proliferation in invasive ductal breast cancer tissues, may have therapeutic implications.

External breast prosthesis use: experiences and views of women with breast cancer, breast care nurses, and prosthesis fitters

After mastectomy, the provision of an appropriate breast prosthesis can help to improve body image and quality of life and reduce associated emotional distress. Although up to 90% of women use an external breast prosthesis after mastectomy, little is known about their experiences and satisfaction with breast prosthesis use. Focus groups were conducted with women who had been fitted with an external breast prosthesis, breast care nurses, and prosthesis fitters to explore women's experiences of prosthesis use. Qualitative thematic content analysis of focus group transcripts indicated that whereas women's initial reaction to the prosthesis generally was negative, this improved over time. Provision of adequate information and support, characteristics of the fitter and the fitting experience, and relationships with breast care nurses and prosthesis fitters were important to women's acceptance and satisfaction with their prosthesis. The study results highlighted the key role that breast care nurses play and the underestimation of the prosthesis fitter's role. Common themes concerning the impact of prosthesis use included body image, appearance, and feminine identity. These findings have important implications for professionals involved in the delivery of breast prostheses services.

The breast cancer related burden of morbidity and mortality in six European coutries

Background: The burden of breast cancer expressed in Disability Adjusted Life Years (DALYs) was compared for six European countries and its sensitivity to different sources of variation examined. Methods: DALYs were calculated using country-specific epidemiological data and European Disability Weights. Epidemiological data for 1996 were obtained for Denmark, England and Wales, France, the Netherlands, Spain and Sweden. Disability weights were empirically derived. Results:  Denmark and the Netherlands lost the largest number of DALYs (approximately 1100 DALYs per 100,000 women). They were followed by England (87% of the Danish burden), France (72%), Sweden (68%) and Spain (67%). 70 to 80% of the burden was caused by mortality. Cross-national variation in disease epidemiology was the largest source of variation in the burden of breast cancer. Variation in disability weights and uncertainty in epidemiological data had smaller effects. Conclusion: To compare the burden of breast cancer and most other types of cancer mortality rates provide sufficient information.

Ets2 maintains hTERT gene expression and breast cancer cell proliferation by interacting with c-Myc

Human telomerase reverse transcriptase (hTERT) underlies cancer cell immortalization, and the expression of hTERT is regulated strictly at the gene transcription. Here, we report that transcription factor Ets2 is required for hTERT gene expression and breast cancer cell proliferation. Silencing Ets2 induces a decrease of hTERT gene expression and increase in human breast cancer cell death. Reconstitution with recombinant hTERT rescues the apoptosis induced by Ets2 depression. In vitro and in vivo analyses show that Ets2 binds to the EtsA and EtsB DNA motifs on the hTERT gene promoter. Mutation of either Ets2 binding site reduces the hTERT promoter transcriptional activity. Moreover, Ets2 forms a complex with c-Myc as demonstrated by co-immunoprecipitation and glutathione S-transferase pulldown assays. Immunological depletion of Ets2, or mutation of the EtsA DNA motif, disables c-Myc binding to the E-box, whereas removal of c-Myc or mutation of the E-box also compromises Ets2 binding to EtsA. Thus, hTERT gene expression is maintained by a mechanism involving Ets2 interactions with the c-Myc transcription factor and the hTERT gene promoter, a protein-DNA complex critical for hTERT gene expression and breast cancer cell proliferation.

Dietary patterns across the life course, mammographic density and implications for breast cancer : results from a British prospective cohort

Background : Previous epidemiological studies have investigated the relationship between individual nutrients such as vitamin D and vitamin B12 and mammographic density, a strong marker of breast cancer risk [1], with varied results. There has been limited research on overall dietary patterns and most studies have focused on adult dietary patterns [2]. We examine prospective data to determine whether dietary patterns from childhood to adult life affect mammographic density.

Methods : The Medical Research Council National Survey of Health and Development is a national representative sample of 2,815 men and 2,547 women followed since their birth in March 1946 [3]. A wealth of medical and social data has been collected in over 25 follow-ups by home visits, medical examinations and postal questionnaires. Dietary intakes at age 4 years were determined by 24-hour recalls and in adulthood (ages 36, 43 years) by 5-day food records. Copies of the mammograms (two views for each breast) taken when the women were closest to age 50 years were obtained from the relevant NHS centres. A total of 1,319 women were followed up since birth in 1946 for whom a mammogram at age 50 years was retrieved, and the percentage mammographic density was measured using the computer-assisted threshold method for all 1,161 women. Breast cancer incidence for the whole cohort is being ascertained through the National Health Service Central Register.

Statistical analysis : Reduced rank regression analysis, a relatively new approach to dietary pattern analysis, is being used to identify dietary patterns associated with mammographic density [4]. This approach identifies patterns in food intake that are predictive of an intermediate outcome of the disease process, such as mammographic density, and subsequently examines the relationship between the identified dietary patterns and breast cancer risk.

Results : Preliminary analyses so far suggest that variations in dietary patterns in adulthood might explain more than 10% of the variation in percentage mammographic density at age 50 years (age 36 years: 13%; age 43 years: 14%), with variations in patterns in childhood explaining slightly less. Further work is being carried out on the characteristics of these dietary patterns and their effects on percentage mammographic density and its two components (that is, absolute areas of dense and nondense tissues) and on breast cancer risk, after adjusting for socioeconomic status, anthropometric variables and reproductive factors.

Conclusion : The present study will provide for the first time information on the relationship between dietary patterns across the life course and mammographic density, and will help to clarify the pathways through which diet may affect breast cancer risk.

Evaluation of advanced breast cancer multidisciplinary team meatings

Background: Multidisciplinary team meetings (MDMs) have become an important decision-making forum in oncology. These meetings bring together expertise from each relevant field to improve continuity of care and health care outcomes for cancer patients. However there is a lack of evidence demonstrating the effectiveness of MDT meetings in improving cancer patient outcomes. The aim of this study was to explore the perceived value and potential usefulness of multidisciplinary team meetings for patients with advanced breast cancer (ABC).

Methods: ABC MDMs have been conducted since 2002 at two sites of Eastern Health, the second largest health service in Melbourne. Attendees were invited to complete a confidential questionnaire in November 2007 that comprised seven areas aimed to assess their judgment of how well the MDMs have improved patient management, including medical recommendations, psychosocial care, palliative care, community care, and team development. Average scores were calculated for improvement of each area.

Results: A total of 16 (69%) health practitioners participated in the survey, with main representation from nursing (37%), allied health (25%) and medicine (19%). Preliminary results indicate that the broad areas members reported the meeting had improved patient outcomes were in palliative care and medical management. Specific areas of perceived improvement were medical outcomes for patients; early referral to palliative care services; confirmation of diagnosis; referral to supportive care; and appropriateness of palliative care referrals. Conversely, the area that had least improved was community care, as there was no input from GPs or community services other than palliative care. Attendance by GPs and radiologists were considered important for further improving medical outcomes for patients.

Conclusions: This study demonstrates the perceived value of the MDT approach in the care of ABC patients, particularly in improving patient outcomes. The next stage of this research is to conduct a survey of ABC patient satisfaction level.

Psychosocial factors and survival of young women with breast cancer: a population-based prospective cohort study

Purpose: Most women with early-stage breast cancer believe that psychosocial factors are an important influence over whether their cancer will recur. Studies of the issue have produced conflicting results.

Patients and Methods: A population-based sample of 708 Australian women diagnosed before age 60 years with nonmetastatic breast cancer was observed for a median of 8.2 years. Depression and anxiety, coping style, and social support were assessed at a median of 11 months after diagnosis. Hazard ratios for distant disease-free survival (DDFS) and overall survival (OS) associated with psychosocial factors were estimated separately using Cox proportional hazards survival models, with and without adjustment for known prognostic factors.

Results: Distant recurrence occurred in 209 (33%) of 638 assessable patients, and 170 (24%) of 708 patients died during the follow-up period. There were no statistically significant associations between any of the measured psychosocial factors and DDFS or OS from the adjusted analyses. From unadjusted analyses, associations between greater anxious preoccupation and poorer DDFS and OS were observed (P = .02). These associations were no longer evident after adjustment for established prognostic factors; greater anxious preoccupation was associated with younger age at diagnosis (P = .03), higher tumor grade (P = .02), and greater number of involved axillary nodes (P = .008).

Conclusion: The findings do not support the measured psychosocial factors being an important influence on breast cancer outcomes. Interventions for adverse psychosocial factors are warranted to improve quality of life but should not be expected to improve survival.

Analytical relationship between family history and genetic and environmental risks, with application to female breast cancer

It is well established in genetic epidemiology that family history is an important indicator of familial aggregation of disease in a family. A strong genetic risk factor or an environmental risk factor with high familial correlation can result in a strong family history. In this paper, family history refers to the number of first-degree relatives affected with the disease. Cui and Hopper (Journal of Epidemiology and Biostatistics 2001; 6: 331-342) proposed an analytical relationship between family history and relevant genetic parameters. In this paper we expand the relationship to both genetic and environmental risk factors. We established a closed-form formula for family history as a function of genetic and environmental parameters which include genetic and environmental relative risks, genotype frequency, prevalence and familial correlation of the environmental risk factor. The relationship is illustrated by an example of female breast cancer in Australia. For genetic and environmental relative risks less than 10, most of the female breast cancer cases occur between the age of 40 and 60 years. A higher genetic or environmental relative risk will move the peak of the distribution to a younger age. A more common disease allele or more prevalent environmental risk factor will move the peak to an older age. For a proband with breast cancer, it is most likely (with probability ge80%) that none of her first-degree relatives is affected with the disease. To enable the probability of having a positive family history to reach 50%, the environmental relative risks must be extremely as high as 100, the familial correlation as high as 0.8 and the prevalence as low as 0.1. For genetic risk alone, even the relative risk is as high as 100, the probability of having a positive family history can only reach about 30%. This suggests that the environmental risk factor seems to play a more important role in determining a strong family history than the genetic risk factor.

Regressive logistic and proportional hazards disease models for within-family analyses of measured genotypes, with application to a CYP17 polymorphism and breast cancer

Various statistical methods have been proposed to evaluate associations between measured genetic variants and disease, including some using family designs. For breast cancer and rare variants, we applied a modified segregation analysis method that uses the population cancer incidence and population-based case families in which a mutation is known to be segregating. Here we extend the method to a common polymorphism, and use a regressive logistic approach to model familial aggregation by conditioning each individual on their mother's breast cancer history. We considered three models: 1) class A regressive logistic model; 2) age-of-onset regressive logistic model; and 3) proportional hazards familial model. Maximum likelihood estimates were calculated using the software MENDEL. We applied these methods to data from the Australian Breast Cancer Family Study on the CYP17 5UTR TC MspA1 polymorphism measured for 1,447 case probands, 787 controls, and 213 relatives of case probands found to have the CC genotype. Breast cancer data for first- and second-degree relatives of case probands were used. The three methods gave consistent estimates. The best-fitting model involved a recessive inheritance, with homozygotes being at an increased risk of 47% (95% CI, 28-68%). The cumulative risk of the disease up to age 70 years was estimated to be 10% or 22% for a CYP17 homozygote whose mother was unaffected or affected, respectively. This analytical approach is well-suited to the data that arise from population-based case-control-family studies, in which cases, controls and relatives are studied, and genotype is measured for some but not all subjects.

Genome - wide association study identifies novel breast cancer susceptibility loci

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r² > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10^-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Age-specific norms and determinants of anxiety and depression in 731 women with breast cancer recruited through a population-based cancer registry

The aim of this study was to determine population norms and determinants of anxiety and depression in a population-based sample of 731 women with breast cancer (aged 23–60 years) with the Hospital Anxiety and Depression scale (HADS). The prevalence of ‘probable’ psychological morbidity due to anxiety was 23% and due to depression was 3%. When the women identified as ‘possible’ cases were included, the respective proportions were 45 and 12%. Higher anxiety was present in younger, less educated women not born in Australia. There was no clear pattern of risk factors for depression. These population-based findings highlight the need for clinicians to be aware that age, education and country of birth may identify a particularly vulnerable subgroup. While brief scales such as the HADS are limited in their ability to accurately predict a clinical diagnosis, high scores identify those who may warrant referral for clinical evaluation.