Is cholesterol a risk factor for breast cancer incidence and outcome?

Cholesterol plays important roles in many physiological processes, including cell membrane structure and function, hormone synthesis, and the regulation of cellular homeostasis. The role of cholesterol in breast cancer is complex, and some studies have suggested that elevated cholesterol levels may be associated with an increased risk of developing breast cancer, while others have found no significant association. On the other hand, other studies have shown that, for total cholesterol and plasma HDL-associated cholesterol levels, there was inverse association with breast cancer risk. One possible mechanism by which cholesterol may contribute to breast cancer risk is as a key precursor of estrogen. Other potential mechanisms by which cholesterol may contribute to breast cancer risk include its role in inflammation and oxidative stress, which have been linked to cancer progression. Cholesterol has also been shown to play a role in signaling pathways regulating the growth and proliferation of cancer cells. In addition, recent studies have shown that cholesterol metabolism can generate tumor promoters such as cholesteryl esters, oncosterone, 27-hydroxycholesterol but also tumor suppressor metabolites such as dendrogenin A. This review summarizes some of the most important clinical studies that have evaluated the role of cholesterol or its derivatives in breast cancer. It also addresses the role of cholesterol and its derivatives at the cellular level.

Trajectories of physical and mental functioning over 25 years before onset of frailty: results from the Whitehall II cohort study.

BACKGROUND: Research on frailty, a major contributor to heterogeneity in health, is undertaken on older adults although the processes leading to frailty are likely to begin earlier in the life course. Using repeat data spanning 25 years, we examined changes in physical and mental functioning before the onset of frailty, defined using Fried's frailty phenotype (FFP). METHODS: Functioning was measured using the Short-Form 36 General Health Survey (SF-36) on nine occasions from 1991 (age range 40-63 years) to 2015 (age range 63-85 years). The poorest of four FFP scores from 2002, 2007, 2012 and 2015 was used to classify participants as frail, pre-frail, or robust. We used linear mixed models with a backward timescale such that time 0 was the person-specific date of frailty classification for frail and pre-frail participants and the end of follow-up for robust participants. Analyses adjusted for socio-demographic factors, health behaviours, body mass index and multi-morbidity status were used to compare SF-36 physical (PCS) and mental (MCS) component summary scores over 25 years before time 0 as a function of FFP classification, with estimates extracted at time 0, -5, -10, -15, -20 and -25 years. We also used illness-death models to examine the prospective association between SF-36 component summary scores at age 50 and incident FFP-defined frailty. RESULTS: Among 7044 participants of the Whitehall II cohort study included in the analysis [29% female, mean age 49.7 (SD = 6.0) at baseline in 1991], 2055 (29%) participants remained robust, and 4476 (64%) became pre-frail and 513 (7%) frail during follow-up. Frail compared with robust participants had lower SF-36 scores at t = -25 before onset of frailty with a difference of 3.4 [95% confidence interval (CI) 1.6, 5.1] in PCS and 1.8 (-0.2, 3.8) in MCS. At t = 0, the differences increased to 11.5 (10.5, 12.5) and 9.1 (8.0, 10.2), respectively. The differences in SF-36 between the robust and pre-frail groups, although smaller [at t = 0, 1.7 (1.2, 2.2) in PCS and 4.0 (3.4, 4.5) in MCS], were already observed 20 and 25 years, respectively, before the onset of pre-frailty. Prospective analyses showed that at age 50, scores in the bottom quartiles of PCS [hazard ratio (HR) compared with the top quartile = 2.39, 95% CI 1.85, 3.07] and MCS [HR = 1.49 (1.15, 1.93)] were associated with a higher risk of FFP-defined frailty at older ages. CONCLUSIONS: Differences in trajectories of physical and mental functioning in individuals who developed physical frailty at older ages were observable 25 years before onset of FFP-defined frailty. These findings highlight the need for a life course approach in efforts to prevent frailty.

Association of sleep duration at age 50, 60, and 70 years with risk of multimorbidity in the UK: 25-year follow-up of the Whitehall II cohort study.

BACKGROUND: Sleep duration has been shown to be associated with individual chronic diseases but its association with multimorbidity, common in older adults, remains poorly understood. We examined whether sleep duration is associated with incidence of a first chronic disease, subsequent multimorbidity and mortality using data spanning 25 years. METHODS AND FINDINGS: Data were drawn from the prospective Whitehall II cohort study, established in 1985 on 10,308 persons employed in the London offices of the British civil service. Self-reported sleep duration was measured 6 times between 1985 and 2016, and data on sleep duration was extracted at age 50 (mean age (standard deviation) = 50.6 (2.6)), 60 (60.3 (2.2)), and 70 (69.2 (1.9)). Incidence of multimorbidity was defined as having 2 or more of 13 chronic diseases, follow-up up to March 2019. Cox regression, separate analyses at each age, was used to examine associations of sleep duration at age 50, 60, and 70 with incident multimorbidity. Multistate models were used to examine the association of sleep duration at age 50 with onset of a first chronic disease, progression to incident multimorbidity, and death. Analyses were adjusted for sociodemographic, behavioral, and health-related factors. A total of 7,864 (32.5% women) participants free of multimorbidity had data on sleep duration at age 50; 544 (6.9%) reported sleeping ≤5 hours, 2,562 (32.6%) 6 hours, 3,589 (45.6%) 7 hours, 1,092 (13.9%) 8 hours, and 77 (1.0%) ≥9 hours. Compared to 7-hour sleep, sleep duration ≤5 hours was associated with higher multimorbidity risk (hazard ratio: 1.30, 95% confidence interval = 1.12 to 1.50; p < 0.001). This was also the case for short sleep duration at age 60 (1.32, 1.13 to 1.55; p < 0.001) and 70 (1.40, 1.16 to 1.68; p < 0.001). Sleep duration ≥9 hours at age 60 (1.54, 1.15 to 2.06; p = 0.003) and 70 (1.51, 1.10 to 2.08; p = 0.01) but not 50 (1.39, 0.98 to 1.96; p = 0.07) was associated with incident multimorbidity. Among 7,217 participants free of chronic disease at age 50 (mean follow-up = 25.2 years), 4,446 developed a first chronic disease, 2,297 progressed to multimorbidity, and 787 subsequently died. Compared to 7-hour sleep, sleeping ≤5 hours at age 50 was associated with an increased risk of a first chronic disease (1.20, 1.06 to 1.35; p = 0.003) and, among those who developed a first disease, with subsequent multimorbidity (1.21, 1.03 to 1.42; p = 0.02). Sleep duration ≥9 hours was not associated with these transitions. No association was found between sleep duration and mortality among those with existing chronic diseases. The study limitations include the small number of cases in the long sleep category, not allowing conclusions to be drawn for this category, the self-reported nature of sleep data, the potential for reverse causality that could arise from undiagnosed conditions at sleep measures, and the small proportion of non-white participants, limiting generalization of findings. CONCLUSIONS: In this study, we observed short sleep duration to be associated with risk of chronic disease and subsequent multimorbidity but not with progression to death. There was no robust evidence of an increased risk of chronic disease among those with long sleep duration at age 50. Our findings suggest an association between short sleep duration and multimorbidity.

Ten-Year Trends in Sales of Alzheimer Disease Drugs in France Compared With Sales in Germany, Spain, and the UK.

This cross-sectional study analyzes 10-year trends in sales of Alzheimer disease drugs in France compared with trends in the UK, Spain, and Germany.

Association between age at onset of multimorbidity and incidence of dementia: 30 year follow-up in Whitehall II prospective cohort study.

OBJECTIVE: To examine the association of midlife and late life multimorbidity, including severity of multimorbidity, with incident dementia. DESIGN: Prospective cohort study. SETTING: Civil service departments in London (Whitehall II study, study inception in 1985-88). PARTICIPANTS: 10 095 participants, aged 35 to 55 at baseline. MAIN OUTCOME MEASURE: Incident dementia at follow-up between 1985 and 2019. Cause specific Cox proportional hazards regression was used to examine the association of multimorbidity overall and at age 55, 60, 65, and 70 with subsequent dementia, taking into account the competing risk of death. RESULTS: The prevalence of multimorbidity (≥2 chronic diseases) was 6.6% (655/9937) at age 55 and 31.7% (2464/7783) at age 70; 639 cases of incident dementia occurred over a median follow-up of 31.7 years. After adjustment for sociodemographic factors and health behaviours, multimorbidity at age 55 was associated with subsequent risk of dementia (difference in incidence rate per 1000 person years 1.56, 95% confidence interval 0.62 to 2.77; hazard ratio 2.44, 95% confidence interval 1.82 to 3.26). The association weakened progressively with older age at onset of multimorbidity. At age 65, onset of multimorbidity before age 55 was associated with 3.86 (1.80 to 6.52) per 1000 person years higher incidence of dementia (hazard ratio 2.46, 1.80 to 2.26) and onset between 60 and 65 was associated with 1.85 (0.64 to 3.39) per 1000 person years higher incidence (1.51, 1.16 to 1.97). Severity of multimorbidity (≥3 chronic diseases) at age 55 was associated with a 5.22 (1.14 to 11.95) per 1000 person years higher incidence of dementia (hazard ratio 4.96, 2.54 to 9.67); the same analyses at age 70 showed 4.49 (2.33 to 7.19) per 1000 person years higher incidence (1.65, 1.25 to 2.18). CONCLUSION: Multimorbidity, particularly when onset is in midlife rather than late life, has a robust association with subsequent dementia. The increasingly younger age at onset of multimorbidity makes prevention of multimorbidity in people with a first chronic disease important.

Five-Year Dynamic Prediction of Dementia Using Repeated Measures of Cognitive Tests and a Dependency Scale.

The progression of dementia prevalence over the years and the lack of efficient treatments to stop or reverse the cognitive decline make dementia a major public health challenge in the developed world. Identifying people at high risk of developing dementia could improve the treatment of these patients and help select the target population for preventive clinical trials. We used joint modeling to build a dynamic prediction tool of dementia based on the change over time of 2 neurocognitive tests (the Mini-Mental State Examination and the Isaacs Set Tests) as well as an autonomy scale (the Instrumental Activities of Daily Living). The model was estimated with data from the French cohort Personnes Agées QUID (1988-2015) and validated both by cross-validation and externally with data from the French Three City cohort (1999-2018). We evaluated its predictive abilities through area under the receiver operating characteristics curve and Brier score, accounting for right censoring and competing risk of death, and obtained an average area under the curve value of 0.95 for the risk of dementia in the next 5 or 10 years. This tool is able to discriminate a high-risk group of people from the rest of the population. This could be of help in clinical practice and research.

Terminal decline in objective and self-reported measures of motor function before death: 10 year follow-up of Whitehall II cohort study.

OBJECTIVES: To examine multiple objective and self-reported measures of motor function for their associations with mortality. DESIGN: Prospective cohort study. SETTING: UK based Whitehall II cohort study, which recruited participants aged 35-55 years in 1985-88; motor function component was added at the 2007-09 wave. PARTICIPANTS: 6194 participants with motor function measures in 2007-09 (mean age 65.6, SD 5.9), 2012-13, and 2015-16. MAIN OUTCOME MEASURES: All cause mortality between 2007 and 2019 in relation to objective measures (walking speed, grip strength, and timed chair rises) and self-reported measures (physical component summary score of the SF-36 and limitations in basic and instrumental activities of daily living (ADL)) of motor function. RESULTS: One sex specific standard deviation poorer motor function in 2007-09 (cases/total, 610/5645) was associated with an increased mortality risk of 22% (95% confidence interval 12% to 33%) for walking speed, 15% (6% to 25%) for grip strength, 14% (7% to 23%) for timed chair rises, and 17% (8% to 26%) for physical component summary score over a mean 10.6 year follow-up. Having basic/instrumental ADL limitations was associated with a 30% (7% to 58%) increased mortality risk. These associations were progressively stronger when measures were drawn from 2012-13 (mean follow-up 6.8 years) and 2015-16 (mean follow-up 3.7 years). Analysis of trajectories showed poorer motor function in decedents (n=484) than survivors (n=6194) up to 10 years before death for timed chair rises (standardised difference 0.35, 95% confidence interval 0.12 to 0.59; equivalent to a 1.2 (men) and 1.3 (women) second difference), nine years for walking speed (0.21, 0.05 to 0.36; 5.5 (men) and 5.3 (women) cm/s difference), six years for grip strength (0.10, 0.01 to 0.20; 0.9 (men) and 0.6 (women) kg difference), seven years for physical component summary score (0.15, 0.05 to 0.25; 1.2 (men) and 1.6 (women) score difference), and four years for basic/instrumental ADL limitations (prevalence difference 2%, 0% to 4%). These differences increased in the period leading to death for timed chair rises, physical component summary score, and ADL limitations. CONCLUSION: Motor function in early old age has a robust association with mortality, with evidence of terminal decline emerging early in measures of overall motor function (timed chair rises and physical component summary score) and late in basic/instrumental ADL limitations.

Development of a Novel High-Performance Thin Layer Chromatography-Based Method for the Simultaneous Quantification of Clinically Relevant Lipids from Cells and Tissue Extracts.

Lipids such as cholesterol, triacylglycerols, and fatty acids play important roles in the regulation of cellular metabolism and cellular signaling pathways and, as a consequence, in the development of various diseases. It is therefore important to understand how their metabolism is regulated to better define the components involved in the development of various human diseases. In the present work, we describe the development and validation of a high-performance thin layer chromatography (HPTLC) method allowing the separation and quantification of free cholesterol, cholesteryl esters, nonesterified fatty acids, and triacylglycerols. This method will be of interest as the quantification of these lipids in one single assay is difficult to perform.

Apolipoprotein-mediated regulation of lipid metabolism induces distinctive effects in different types of breast cancer cells.

BACKGROUND: The highest incidence of breast cancer is in the Western world. Several aspects of the Western lifestyle are known risk factors for breast cancer. In particular, previous studies have shown that cholesterol levels can play an important role in the regulation of tumor progression. METHODS: In the present study, we modulated cholesterol metabolism in the human breast cancer cell lines MCF-7 and MDA-MB-231 using a genetic approach. Apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE) were expressed in these cell lines to modulate cholesterol metabolism. The effects of these apolipoproteins on cancer cell properties were examined. RESULTS: Our results show that both apolipoproteins can regulate cholesterol metabolism and can control the epithelial-to-mesenchymal transition process. However, these effects were different depending on the cell type. We show that expressing apoA-I or apoE stimulates proliferation, migration, and tumor growth of MCF-7 cells. However, apoA-I or apoE reduces proliferation and migration of MDA-MB-231 cells. CONCLUSIONS: These data suggest that modulating sterol metabolism may be most effective at limiting tumor progression in models of triple-negative cancers.

Oxidized Products of α-Linolenic Acid Negatively Regulate Cellular Survival and Motility of Breast Cancer Cells.

Despite recent advances in our understanding of the biological processes leading to the development and progression of cancer, there is still a need for new and effective agents to treat this disease. Phytoprostanes (PhytoPs) and phytofurans (PhytoFs) are non-enzymatically oxidized products of α-linolenic acid that are present in seeds and vegetable oils. They have been shown to possess anti-inflammatory and apoptosis-promoting activities in macrophages and leukemia cells, respectively. In this work, seven PhytoPs (PP1-PP7) and one PhytoFs (PF1) were evaluated for their cytotoxic, chemosensitization, and anti-migratory activities using the MCF-7 and MDA-MB-231 breast cancer cell lines. Among the tested compounds, only three PhytoPs had a significant effect on cell viability compared to the control group: Ent-9-L1-PhytoP (PP6) decreased cell viability in both cell lines, while 16-F1t-PhytoP (PP1) and 9-L1-PhytoP (PP5) decreased viability of MCF-7 and MDA-MB-231 cells, respectively. When combined with a sub-cytotoxic dose of doxorubicin, these three PhytoPs displayed significantly enhanced cytotoxic effects on MCF-7 cells while the chemotherapeutic drug alone had no effect. In cellular motility assays, Ent-9-(RS)-12-epi-ST-Δ10-13-PhytoF could significantly inhibit cellular migration of MDA-MB-231 cells. In addition, Ent-9-(RS)-12-epi-ST-Δ10-13-PhytoF also enhanced cellular adhesion of MDA-MB-231 cells.

SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer.

Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI), which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high-density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI's function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies.