Amtul R. Carmichael

Physical activity, risk of death and recurrence in breast cancer survivors: A systematic review and meta-analysis of epidemiological studies

Abstract Strong evidence exists supporting the effect of lack of physical activity on the risk of developing breast cancer. However, studies examining the effects of physical activity on breast cancer outcomes, including survival and prognosis have been inconclusive. Therefore, the aim of the current study was to provide a systematic review and meta-analysis of studies investigating the association between physical activity and breast cancer recurrence and death. Methods. PubMed, EMBASE, and CENTRAL databases were searched up to 18 October 2014. Reference lists of retrieved articles and relevant previous reviews were also searched. Observational studies that reported risk estimates for all-cause and/or breast cancer-related death and/or breast cancer recurrences by levels of physical activity, were included in the review. Random effects models were used to calculate pooled hazard ratios (HR) and 95% confidence intervals (CI) and to incorporate variation between studies. The Newcastle-Ottawa scale was used to critically appraise the risk of bias across studies. Results. Twenty-two prospective cohort studies were eligible in this meta-analysis. During average follow-up periods ranging from 4.3 to 12.7 years there were 123 574 participants, 6898 all-cause deaths and 5462 breast cancer outcomes (i.e. breast cancer-related deaths or recurrences). The average Newcastle-Ottawa score was six stars (range 4–8). Compared to those who reported low/no lifetime recreational pre-diagnosis physical activity, participants who reported high lifetime recreational pre-diagnosis physical activity levels had a significantly lower risk of all-cause (HR = 0.82, 95% CI 0.70–0.96, p < 0.05) and breast cancer-related death (HR = 0.73, 95% CI 0.54–0.98, p < 0.05). Significant risk reductions for all-cause and breast cancer-related death was also demonstrated for more recent pre-diagnosis recreational physical activity (HR = 0.73, 95% CI 0.65–0.82, p < 0.001; and HR = 0.84, 95% CI 0.73–0.97, p < 0.05, respectively), post-diagnosis physical activity (HR = 0.52, 95% CI 0.43–0.64, p < 0.01; and HR = 0.59, 95% CI 0.45–0.78, p < 0.05, respectively) and meeting recommended physical activity guidelines (i.e. ≥ 8 MET-h/wk) post-diagnosis (HR = 0.54, 95% CI 0.38–0.76, p < 0.01; and HR = 0.67, 95% CI 0.50–0.90, p < 0.01, respectively). However, there was evidence of heterogeneity across lifetime recreational pre- and post-diagnosis physical activity analyses. Both pre-diagnosis (lifetime and more recent combined) and post-diagnosis physical activity were also associated with reduced risk of breast cancer events (breast cancer progression, new primaries and recurrence combined) (HR = 0.72 95% CI 0.56–0.91, p < 0.01; and HR = 0.79, 95% CI 0.63–0.98, p < 0.05, respectively). Conclusion. There is an inverse relationship between physical activity and all-cause, breast cancer-related death and breast cancer events. The current meta-analysis supports the notion that appropriate physical activity may be an important intervention for reducing death and breast cancer events among breast cancer survivors.

Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review

BackgroundTumour cells show greater dependency on glycolysis so providing a sufficient and rapid energy supply for fast growth. In many breast cancers, estrogen, progesterone and epidermal growth factor receptor-positive cells proliferate in response to growth factors and growth factor antagonists are a mainstay of treatment. However, triple negative breast cancer (TNBC) cells lack receptor expression, are frequently more aggressive and are resistant to growth factor inhibition. Downstream of growth factor receptors, signal transduction proceeds via phosphatidylinositol 3-kinase (PI3k), Akt and FOXO3a inhibition, the latter being partly responsible for coordinated increases in glycolysis and apoptosis resistance. FOXO3a may be an attractive therapeutic target for TNBC. Therefore we have undertaken a systematic review of FOXO3a as a target for breast cancer therapeutics.MethodsArticles from NCBI were retrieved systematically when reporting primary data about FOXO3a expression in breast cancer cells after cytotoxic drug treatment.ResultsIncreased FOXO3a expression is common following cytotoxic drug treatment and is associated with apoptosis and cell cycle arrest. There is some evidence that metabolic enzyme expression is also altered and that this effect is also elicited in TNBC cells. FOXO3a expression serves as a positive prognostic marker, especially in estrogen (ER) receptor positive cells.DiscussionFOXO3a is upregulated by a number of receptor-dependent and -independent anti-cancer drugs and associates with apoptosis. The identification of microRNA that regulate FOXO3a directly suggest that it offers a tangible therapeutic target that merits wider evaluation.

An aqueous extract of Fagonia cretica induces DNA damage, cell cycle arrest and apoptosis in breast cancer cells via FOXO3a and p53 expression

Background Plants have proved to be an important source of anti-cancer drugs. Here we have investigated the cytotoxic action of an aqueous extract of Fagonia cretica, used widely as a herbal tea-based treatment for breast cancer. Methodology/Principal Findings Using flow cytometric analysis of cells labeled with cyclin A, annexin V and propidium iodide, we describe a time and dose-dependent arrest of the cell cycle in G0/G1 phase of the cell cycle and apoptosis following extract treatment in MCF-7 (WT-p53) and MDA-MB-231 (mutant-p53) human breast cancer cell lines with a markedly reduced effect on primary human mammary epithelial cells. Analysis of p53 protein expression and of its downstream transcription targets, p21 and BAX, revealed a p53 associated growth arrest within 5 hours of extract treatment and apoptosis within 24 hours. DNA double strand breaks measured as γ-H2AX were detected early in both MCF-7 and MDA-MB-231 cells. However, loss of cell viability was only partly due to a p53-driven response; as MDA-MB-231 and p53-knockdown MCF-7 cells both underwent cell cycle arrest and death following extract treatment. p53-independent growth arrest and cytotoxicity following DNA damage has been previously ascribed to FOXO3a expression. Here, in MCF-7 and MDA-MB-231 cells, FOXO3a expression was increased significantly within 3 hours of extract treatment and FOXO3 siRNA reduced the extract-induced loss of cell viability in both cell lines. Conclusions/Significance Our results demonstrate for the first time that an aqueous extract of Fagonia cretica can induce cell cycle arrest and apoptosis via p53-dependent and independent mechanisms, with activation of the DNA damage response. We also show that FOXO3a is required for activity in the absence of p53. Our findings indicate that Fagonia cretica aqueous extract contains potential anti-cancer agents acting either singly or in combination against breast cancer cell proliferation via DNA damage-induced FOXO3a and p53 expression.

Physical activity and breast cancer outcome: a brief review of evidence, current practice and future direction.

There have been several publications of large scale studies with long-term follow up addressing the role of physical activity in the management of breast cancer. Of the twelve studies specifically addressing the effect of physical activity on breast cancer survival, eight showed a statistically significant 50% risk reduction in breast cancer mortality in women who engaged in moderate intensity physical activity before and after their diagnosis of breast cancer. Four smaller studies demonstrated no benefit. Almost all of these observational studies predominantly involved white, professional women from North America and Europe. The positive effects of physical activity were seen for all stages of cancer, with the greatest benefit in steroid receptor positive breast tumours. These studies relied on self-reported questionnaires for recording the levels of physical activity. Despite including thousands of patients, published studies offer no data related to the optimum type, duration and timing of physical activity. Only a few studies provided objective data on physical activity, cardio-respiratory and general fitness. Thus, potential role of physical activity in the management of breast cancer remains far from established. If the beneficial effect of physical activity as demonstrated in the observational studies can be replicated in robust, well designed and well-executed prospective randomised controlled trials, this would provide a tremendous opportunity to enhance adjuvant treatment of breast cancer. By adding physical activity to the spectrum of adjuvant therapies offered to women survival from breast cancer may be enhanced.

Obesity in post menopausal women with a family history of breast cancer: prevalence and risk awareness

BackgroundObesity and physical activity are modifiable risk factors in the development of post-menopausal breast cancer. The aim of this study was to assess the level of awareness and prevalence of these factors in women attending family history clinics.MethodsWomen attending the breast cancer family history clinic from 2004 to 2006 completed a questionnaire (SP15 format) about their knowledge of and exposure to various diet and lifestyle factors. All women had been counselled by a Consultant Cancer Geneticist and were given verbal and written information on the effect of life style on breast cancer risk. Responses were analysed using SPSS™ software.ResultsThe response rate was 70% and two thirds of women were post-menopausal. The prevalence of obesity in post-menopausal women was 37% with 40% being overweight. The majority of women consumed a healthy balanced diet. Only 15% of post-menopausal women exercised for more than 4 hours per week. Two-thirds of women correctly stated that obesity increases their breast cancer risk and 73% of these were overweight or obese. Over 87% were correctly aware of the role of family history, 68% of a high fat diet, and 57% of hormone replacement therapy in the development of breast cancer.ConclusionWomen attending family history clinics lead a high risk lifestyle for the development of breast cancer with high prevalence of obesity and low levels of physical activity. A campaign of patient education is needed to promote healthy lifestyle choices, especially physical activity, in these high-risk women.

Granular cell tumour of the soft tissues: a case report and literature review

Granular cell tumours (GCT) of the soft tissues are rare benign tumours but some time may be difficult to distinguish from malignant neoplasms. It is important that clinicians are aware of their existence. We present a new case of GCT of the soft tissues followed by a brief review of literature.

Breast cancer therapy and cardiovascular risk: focus on trastuzumab.

Breast cancer is the most common cancer in the UK. Advances in the methods of early diagnosis as well as newer and more effective treatments have led to improvements of disease-free and overall survival over the last decade. Almost one-third of breast cancers present with an aggressive form characterized by increased expression of human epidermal growth receptor 2 (HER2) proteins. A targeted treatment using monoclonal antibodies against HER2 expression such as trastuzumab has been shown to improve survival. Unfortunately, there is a degree of cardiotoxicity associated with these agents, as inhibition of HER2 pathways can also impair cardioprotective pathways. In the present review, we discuss the mechanisms by which trastuzumab might affect vascular homeostasis leading to endothelial dysfunction. We also provide suggestions for future research examining the effects of trastuzumab on the vasculature in breast cancer.

Obesity and HER 2 overexpression: a common factor for poor prognosis of breast cancer

BackgroundBoth obesity and over-expression of HER II are associated with poor prognosis of breast cancer. In vitro experiments suggest that anti-tumour activity of the anti-obesity drug Orlistat is likely to be due to transcriptional suppression of HER II expression. The overexpression of HER II is also positively correlated with other markers of prognosis of breast cancer such as cathepsin expression.HypothesisThe hypothesis we tested was that the obese women with breast cancer might over-express HER II more often than their lean counterparts to account for the poor prognosis.Patients and methodsOne hundred consecutive patients were included in this study. Their body mass indexes were correlated with overexpression of HER II.ResultsThere was also no association between oestrogen or progesterone receptor positivity and obesity or HER II over expression in premenopausal or post-menopausal women with breast cancer.ConclusionThe present study demonstrated that the poor outcome of breast cancer in obese patients is not due to over expression of HER II.

Breast clinic and life style study BLLISS

BackgroundIndependent, strong and unequivocal evidence suggests that life style factors such as obesity and lack of physical activity along with certain reproductive choices can increase the risk of breast cancer. There are no studies measuring the effectiveness of guidelines from the Department of Health regarding life style choices made by women presenting to breast clinics. The aim of this audit was to study the prevalence of obesity, physical activity and reproductive factors in women referred to breast clinic.Patients and methodsAll patients attending the Breast clinic as new referrals were invited to complete a life style questionnaire. The data was analysed for prevalence of various risk factors for breast cancer. Three hundred and 73 patients completed the questionnaire.ResultsFinal analyses of 373 patients demonstrated that 42% of women performed no exercise and only 24% of patients met Department of Health guideline of 30 minutes of exercise for 5 days a week. Overall 50% of patients were either obese or overweight and 22% of patients had BMI of > 30 kg/m2. The median age of menarche was 13 and 18% of women started their period below the age 12. Twenty one percent of women were nulliparous and 14% had their first live birth after the age of 30. Fourteen percent of patients were on the hormone replacement therapy of which 57% have used hormones for more than 5 years. Twenty two percent of women smoked and 9% of women consumed alcohol 5 days a week of which 13% had more than 4 glasses of alcohol in a day.ConclusionThere is preponderance of high risk life style choices in women attending breast clinic. If these life style options are not modified, there could potentially be a significant rise in the number of breast cancer in West Midlands.

Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells

Abstract Bardoxolone-methyl (BAR) is reported to have anti-inflammatory, anti-proliferative and anti-fibrotic effects. BAR activates Nrf2 and may ameliorate oxidative stress through induction of antioxidant genes. However, off-target effects, probably concentration and NFkB-dependent, have limited the clinical use of BAR. Nrf2 regulates expression of antioxidant and mitochondrial genes and has been proposed as a target for both obesity and breast cancer. Therefore, we explored whether BAR can alter migration and proliferation in the MCF7 cell line and whether metabolic function is affected by BAR. Incubation with BAR caused a time-dependent migratory inhibition and an associated decrease in mitochondrial respiration. Both migratory and mitochondrial inhibition by BAR were further enhanced in the presence of fatty acids. In addition to the activation of Nrf2, BAR altered the expression of target mRNA GCLC and UCP1. After 24 h, BAR inhibited both glycolytic capacity, reserve (p < 0.05) and oxidative phosphorylation (p < 0.001) with an associated increase in mitochondrial ROS and loss of intracellular glutathione in MCF7 cells; however, impairment of mitochondrial activity was prevented by N-acetyl cysteine. The fatty acid, palmitate, increased mitochondrial ROS, impaired migration and oxidative phosphorylation but palmitate toxicity towards MCF7 could not be inhibited by N-acetyl cysteine suggesting that they exert effects through different pathways. BAR-activated AKT, induced DNA damage and inhibited cell proliferation. When the proteasome was inhibited, there was loss of BAR-mediated changes in p65 phosphorylation and SOD2 expression suggesting non-canonical NFkB signaling effects. These data suggest that BAR-induced ROS are important in inhibiting MCF7 migration and metabolism by negatively affecting glycolytic capacity and mitochondrial function.