Circadian rhythms and breast cancer: from molecular level to therapeutic advancements.

BACKGROUND AND OBJECTIVES: Circadian rhythms, the endogenous biological clocks that govern physiological processes, have emerged as pivotal regulators in the development and progression of breast cancer. This comprehensive review delves into the intricate interplay between circadian disruption and breast tumorigenesis from multifaceted perspectives, encompassing biological rhythms, circadian gene regulation, tumor microenvironment dynamics, and genetic polymorphisms. METHODS AND RESULTS: Epidemiological evidence underscores the profound impact of external factors, such as night shift work, jet lag, dietary patterns, and exercise routines, on breast cancer risk and progression through the perturbation of circadian homeostasis. The review elucidates the distinct roles of key circadian genes, including CLOCK, BMAL1, PER, and CRY, in breast cancer biology, highlighting their therapeutic potential as molecular targets. Additionally, it investigates how circadian rhythm dysregulation shapes the tumor microenvironment, fostering epithelial-mesenchymal transition, chronic inflammation, and immunosuppression, thereby promoting tumor progression and metastasis. Furthermore, the review sheds light on the association between circadian gene polymorphisms and breast cancer susceptibility, paving the way for personalized risk assessment and tailored treatment strategies. CONCLUSIONS: Importantly, it explores innovative therapeutic modalities that harness circadian rhythms, including chronotherapy, melatonin administration, and traditional Chinese medicine interventions. Overall, this comprehensive review emphasizes the critical role of circadian rhythms in the pathogenesis of breast cancer and highlights the promising prospects for the development of circadian rhythm-based interventions to enhance treatment efficacy and improve patient outcomes.

Chronobiology of Cancers in the Liver and Gut.

Circadian rhythms dictate the timing of cellular and organismal physiology to maintain homeostasis. Within the liver and gut, circadian rhythms influence lipid and glucose homeostasis, xenobiotic metabolism, and nutrient absorption. Disruption of this orchestrated timing is known to negatively impact human health and contribute to disease progression, including carcinogenesis. Dysfunctional core clock timing has been identified in malignant growths and may be used as a molecular signature of disease progression. Likewise, the circadian clock and its downstream effectors also represent potential for novel therapeutic targets. Here, the role of circadian rhythms in the pathogenesis of cancers of the liver and gut will be reviewed, and chronotherapy and chronopharmacology will be explored as potential treatment options.

Effects of Chronotherapeutic Interventions in Adults With ADHD and Delayed Sleep Phase Syndrome (DSPS) on Regulation of Appetite and Glucose Metabolism.

Background: ADHD is highly comorbid with Delayed Sleep Phase Syndrome (DSPS). Both are associated with obesity and diabetes, which can be caused by long-term dysregulations of appetite and glucose metabolism. This study explores hormones involved in these processes and the effects of chronotherapeutic interventions in a small sample of adults with ADHD and DSPS. Methods: Exploratory, secondary analysis of data from the PhASE study, a three-armed randomized clinical trial, are presented, including 37 adults (18-53 years) with ADHD and DSPS receiving three weeks of 0.5 mg/day (1) placebo, (2) melatonin, or (3) melatonin plus 30 minutes of bright light therapy (BLT). Leptin (appetite-suppressing), ghrelin (appetite-stimulating), insulin, insulin-like growth factor-1 (IGF-1), and glucose were measured from blood collected at 08:00 hours. Salivary cortisol was collected during the first 30 minutes after awakening and self-reported appetite was assessed. Results: Baseline leptin and IGF-1 levels were higher than reference ranges, and ghrelin and cortisol levels were lower, while insulin and glucose were normal. Melatonin treatment decreased leptin and insulin. Other outcomes remained unchanged and melatonin + BLT had no effects. Conclusion: Due to the small sample size and exploratory nature of the study, results should be interpreted with caution. Overall, these results show no strong indications for dysregulation of appetite and glucose metabolism to suggest high risk of obesity and diabetes in this small sample of adults with ADHD and DSPS. However, baseline appetite was suppressed, likely because measurements took place in the early morning which could be considered the biological night for this study population. Melatonin treatment seemed to cause subtle changes in appetite-regulating hormones suggesting increased appetite. Chronotherapeutic treatment may affect appetite-regulating hormones by advancing the biological rhythm and/or altering eating behaviors, but this remains to be investigated in larger samples using detailed food diaries.

Diabetic Neuropathic Pain and Circadian Rhythm: A Future Direction Worthy of Study.

More than half of people with diabetes experience neuropathic pain. Previous research has shown that diabetes patients' neuropathic pain exhibits a circadian cycle, which is characterized by increased pain sensitivity at night. Additional clinical research has revealed that the standard opioid drugs are ineffective at relieving pain and do not change the circadian rhythm. This article describes diabetic neuropathic pain and circadian rhythms separately, with a comprehensive focus on circadian rhythms. It is hoped that this characteristic of diabetic neuropathic pain can be utilized in the future to obtain more effective treatments for it.

Circadian lighting effect for inpatients with schizophrenia: A prospective cohort study.

OBJECTIVES: In schizophrenia, nonspecific lighting likely causes sleep timing disturbances, leading to distress and poorer clinical status. However, the effect of exposure to circadian lighting on psychopathology outcome in schizophrenia remains unknown. Hence, this study aimed to develop such an intervention and investigate its impact on schizophrenia. METHODS: Twenty schizophrenia patients at a psychiatric nursing institute were monitored over 10 weeks, with assessments using the Brief Psychiatric Rating Scale (BPRS) and Mini-Mental State Examination (MMSE) conducted at baseline, weeks 3 (T1), 7 (T2), and 10 (T3). RESULTS: Circadian lighting significantly improved BPRS scores between T1-T2 (p < .05) and T1-T3 (p < .001), with affectivity scores also showing significant enhancements postintervention. Notably, female participants exhibited substantial improvements in BPRS scores from T1 to T3 (p < .01), while male participants demonstrated significant gains in MMSE scores from T1 to T2 (p < .01). CONCLUSIONS: Circadian lighting presents a promising intervention for improving psychiatric outcomes in schizophrenia, with distinct benefits observed across different psychopathological aspects and genders. These findings underscore the potential of lighting chronotherapy in psychiatric clinical practice and warrant further exploration in related research.

A circadian clock regulates the blood-brain barrier across phylogeny.

As the central regulatory system of an organism, the brain is responsible for overseeing a wide variety of physiological processes essential for an organism's survival. To maintain the environment necessary for neurons to function, the brain requires highly selective uptake and elimination of specific molecules through the blood-brain barrier (BBB). As an organism's activities vary throughout the day, how does the BBB adapt to meet the changing needs of the brain? A mechanism is through temporal regulation of BBB permeability via its circadian clock, which will be the focal point of this chapter. To comprehend the circadian clock's role within the BBB, we will first examine the anatomy of the BBB and the transport mechanisms enabling it to fulfill its role as a restrictive barrier. Next, we will define the circadian clock, and the discussion will encompass an introduction to circadian rhythms, the Transcription-Translation Feedback Loop (TTFL) as the mechanistic basis of circadian timekeeping, and the organization of tissue clocks found in organisms. Then, we will cover the role of the circadian rhythms in regulating the cellular mechanisms and functions of the BBB. We discuss the implications of this regulation in influencing sleep behavior, the progression of neurodegenerative diseases, and finally drug delivery for treatment of neurological diseases.

Exploring the interplay between circadian rhythms and prostate cancer: insights into androgen receptor signaling and therapeutic opportunities.

Circadian rhythm disruption is closely related to increased incidence of prostate cancer. Incorporating circadian rhythms into the study of prostate cancer pathogenesis can provide a more comprehensive understanding of the causes of cancer and offer new options for precise treatment. Therefore, this article comprehensively summarizes the epidemiology of prostate cancer, expounds the contradictory relationship between circadian rhythm disorders and prostate cancer risk, and elucidates the relationship between circadian rhythm regulators and the incidence of prostate cancer. Importantly, this article also focuses on the correlation between circadian rhythms and androgen receptor signaling pathways, as well as the applicability of time therapy in prostate cancer. This may prove significant in enhancing the clinical treatment of prostate cancer.

Circadian rhythm disruption and endocrine-related tumors.

This review delved into the intricate relationship between circadian clocks and physiological processes, emphasizing their critical role in maintaining homeostasis. Orchestrated by interlocked clock genes, the circadian timekeeping system regulates fundamental processes like the sleep-wake cycle, energy metabolism, immune function, and cell proliferation. The central oscillator in the hypothalamic suprachiasmatic nucleus synchronizes with light-dark cycles, while peripheral tissue clocks are influenced by cues such as feeding times. Circadian disruption, linked to modern lifestyle factors like night shift work, correlates with adverse health outcomes, including metabolic syndrome, cardiovascular diseases, infections, and cancer. We explored the molecular mechanisms of circadian clock genes and their impact on metabolic disorders and cancer pathogenesis. Specific associations between circadian disruption and endocrine tumors, spanning breast, ovarian, testicular, prostate, thyroid, pituitary, and adrenal gland cancers, are highlighted. Shift work is associated with increased breast cancer risk, with PER genes influencing tumor progression and drug resistance. CLOCK gene expression correlates with cisplatin resistance in ovarian cancer, while factors like aging and intermittent fasting affect prostate cancer. Our review underscored the intricate interplay between circadian rhythms and cancer, involving the regulation of the cell cycle, DNA repair, metabolism, immune function, and the tumor microenvironment. We advocated for integrating biological timing into clinical considerations for personalized healthcare, proposing that understanding these connections could lead to novel therapeutic approaches. Evidence supports circadian rhythm-focused therapies, particularly chronotherapy, for treating endocrine tumors. Our review called for further research to uncover detailed connections between circadian clocks and cancer, providing essential insights for targeted treatments. We emphasized the importance of public health interventions to mitigate lifestyle-related circadian disruptions and underscored the critical role of circadian rhythms in disease mechanisms and therapeutic interventions.

Seizure timing and circadian patterns: a comprehensive bibliographic review / Cronometragem das crises epilépticas e padrões circadianos: uma revisão bibliográfica abrangente

Epilepsy's cyclic nature, increasingly quantified through advancements in continuous electroencephalography (cEEG), reveals robust seizure cycles including circadian, multidien, and circannual rhythms. Understanding these cycles' mechanisms and clinical implications, such as seizure forecasting and optimized treatment timing, is crucial. Despite historical observations, detailed analysis of seizure timing cycles has become feasible only recently, necessitating further research to confirm generalizability and clinical relevance. This paper reviews current literature on circadian rhythms in epilepsy, focusing on temporal seizure patterns and identifying knowledge gaps. A comprehensive review of studies, primarily using PubMed, synthesizes key findings from 20 studies on the temporal dynamics of epileptic activity. Research shows consistent circadian rhythms in seizure activity, with distinct daily peaks. Seizures often follow daily patterns, termed "seizure rush hours," with specific seizure types linked to particular times and influenced by sleep-wake cycles. These findings underscore the importance of understanding temporal patterns in epilepsy. Understanding these rhythms can enhance seizure prediction, diagnosis, and personalized treatment strategies. The significant role of biological rhythms suggests that tailored treatments based on individual circadian profiles could improve patient outcomes and quality of life. Further research is essential to elucidate the mechanisms driving these influences and validate findings across diverse cohorts.

A natureza cíclica da epilepsia, cada vez mais quantificada por meio dos avanços na eletroencefalografia contínua (cEEG), revela ciclos de crises epilépticas (CE) robustos, incluindo ritmos circadianos, multidiários e circanuais. Compreender os mecanismos e as implicações clínicas desses ciclos, como a previsão de CE e a otimização do momento do tratamento, é crucial. Apesar das observações históricas, a análise detalhada dos ciclos de tempo das CE tornou-se viável apenas recentemente, exigindo mais pesquisas para confirmar a generalização e a relevância clínica. Este artigo revisa a literatura atual sobre ritmos circadianos na epilepsia, focando nos padrões temporais das CE e identificando lacunas no conhecimento. Uma revisão abrangente dos estudos, principalmente utilizando o PubMed, sintetiza os principais achados de 20 estudos sobre a dinâmica temporal da atividade epiléptica. A pesquisa mostra ritmos circadianos consistentes na atividade das CE, com picos diários distintos. As CE frequentemente seguem padrões diários, denominados "horários de pico das convulsões" ("seizure rush hours"), com tipos específicos de CE vinculados a determinados horários e influenciados pelos ciclos sono-vigília. Esses achados destacam a importância de entender os padrões temporais na epilepsia. Compreender esses ritmos pode melhorar a previsão, o diagnóstico e as estratégias de tratamento personalizado das CE. O papel significativo dos ritmos biológicos sugere que tratamentos personalizados com base nos perfis circadianos individuais podem melhorar os resultados e a qualidade de vida dos pacientes. Mais pesquisas são essenciais para elucidar os mecanismos que impulsionam essas influências e validar os achados em diversas coortes.

The specificities, influencing factors, and medical implications of bone circadian rhythms.

Physiological processes within the human body are regulated in approximately 24-h cycles known as circadian rhythms, serving to adapt to environmental changes. Bone rhythms play pivotal roles in bone development, metabolism, mineralization, and remodeling processes. Bone rhythms exhibit cell specificity, and different cells in bone display various expressions of clock genes. Multiple environmental factors, including light, feeding, exercise, and temperature, affect bone diurnal rhythms through the sympathetic nervous system and various hormones. Disruptions in bone diurnal rhythms contribute to the onset of skeletal disorders such as osteoporosis, osteoarthritis and skeletal hypoplasia. Conversely, these bone diseases can be effectively treated when aimed at the circadian clock in bone cells, including the rhythmic expressions of clock genes and drug targets. In this review, we describe the unique circadian rhythms in physiological activities of various bone cells. Then we summarize the factors synchronizing the diurnal rhythms of bone with the underlying mechanisms. Based on the review, we aim to build an overall understanding of the diurnal rhythms in bone and summarize the new preventive and therapeutic strategies for bone disorders.

Therapeutic sleep deprivation for major depressive disorder: A randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is treated primarily using antidepressant drugs, but clinical effects may be delayed for weeks to months. This study investigated the efficacy of brief therapeutic sleep deprivation (TSD) for inducing rapid improvements in MDD symptoms. METHODS: From November 2020 to February 2023, 54 inpatients with MDD were randomly allocated to TSD and Control groups. The TSD group (23 cases) remained awake for 36 h, while the Control group (31 cases) maintained regular sleep patterns. All participants continued regular drug therapy. Mood was assessed using the 24-item Hamilton Depression Scale (HAMD-24) at baseline and post-intervention in both groups. In the TSD group, the Visual Analogue Scale (VAS) was utilized to evaluate subjective mood during and after the intervention. Cognitive function was assessed at baseline and post-intervention using the Montreal Cognitive Assessment (MoCA). Objective sleep parameters were recorded in the TSD group by polysomnography. The follow-up period spanned one week. RESULTS: HAMD-24 scores did not differ between groups at baseline or post-intervention. However, the clinical response rate was 34.8 % higher in the TSD group on day 3 post-intervention compared to the Control group (3.2 %), but not sustained by day 7. Moreover, responders demonstrated a faster improvement in the VAS score during TSD than non-responders (p = 0.047). There were no significant differences in MoCA scores or objective sleep parameters between the groups. LIMITATIONS: Small sample size and notable attrition rate. CONCLUSIONS: Therapeutic sleep deprivation can rapidly improve MDD symptoms without influencing sleep parameters or cognitive functions. Assessment of longer-term effects and identification of factors predictive of TSD response are warranted.

Pharmacological Modulation of the Cytosolic Oscillator Affects Glioblastoma Cell Biology.

The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to coordinate behavior and physiology. Circadian disruption can be a contributing factor in the development of metabolic diseases, inflammatory disorders, and higher risk of cancer. Glioblastoma (GBM) is a highly aggressive grade 4 brain tumor that is resistant to conventional therapies and has a poor prognosis after diagnosis, with a median survival of only 12-15 months. GBM cells kept in culture were shown to contain a functional circadian oscillator. In seeking more efficient therapies with lower side effects, we evaluated the pharmacological modulation of the circadian clock by targeting the cytosolic kinases glycogen synthase kinase-3 (GSK-3) and casein kinase 1 ε/δ (CK1ε/δ) with specific inhibitors (CHIR99021 and PF670462, respectively), the cryptochrome protein stabilizer (KL001), or circadian disruption after Per2 knockdown expression in GBM-derived cells. CHIR99021-treated cells had a significant effect on cell viability, clock protein expression, migration, and cell cycle distribution. Moreover, cultures exhibited higher levels of reactive oxygen species and alterations in lipid droplet content after GSK-3 inhibition compared to control cells. The combined treatment of CHIR99021 with temozolomide was found to improve the effect on cell viability compared to temozolomide therapy alone. Per2 disruption affected both GBM migration and cell cycle progression. Overall, our results suggest that pharmacological modulation or molecular clock disruption severely affects GBM cell biology.

Chronotype variability in epilepsy and clinical significance: scoping review.

PURPOSE: Chronotype, which captures a person's daily preferences for activity and sleep, is still a poorly researched area in epilepsy research. Finding common chronotype characteristics in people with epilepsy (PWE) and explaining possible effects on seizure management are the main goals. METHODS: Eleven large-scale investigations from 2010 to 2023 were examined in this scoping review. These studies included 1.167 PWE and 4.657 control subjects. RESULTS: PWE had intermediate chronotypes more often than not. Adult patients were more morning-oriented overall, while pediatric cohorts were variable. Relationships between chronotype and seizure control were limited since only two studies in adults reported this and those results conflicted. An evening-type chronotype was found to be more common in generalized epilepsy than focal. The relationship of chronotype and specific antiseizure medication (ASM) therapy was not investigated. CONCLUSIONS: The majority of PWE displayed an intermediate chronotype, but analyses based on age showed more nuanced trends, with children displaying variable patterns, adults generally tending toward morningness, and generalized epilepsy being associated with eveningness. This review underscores the importance of more research on the complex connections between epilepsy outcomes and chronotype. It emphasizes the need to study larger samples of PWE with carefully documented seizure control and ASM therapy, including dose and timing of administration to better understand the role of chronotype on epilepsy outcomes.

Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes: the Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study.

Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes. Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype. Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14-1.86] and 0.96 [95% CI 0.70-1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18-2.22] and 0.66 [95% CI 0.44-1.00] per hour of MSFsc, respectively; interaction p < 0.001). No interaction between chronotype and antihypertensive dosing time was observed for stroke events. Interpretation: Alignment of dosing time of usual antihypertensives with personal chronotype could lower the incidence of non-fatal MI compared to a 'misaligned' dosing time regimen. Future studies are warranted to establish whether synchronizing administration time of antihypertensive therapy with individual chronotype reduces risk of MI. Funding: The TIME study was funded by the British Heart Foundation (CS/14/1/30659) with support from the British and Irish Hypertension Society.

Chronotherapy involving rosiglitazone regulates the phenotypic switch of vascular smooth muscle cells by shifting the phase of TNF-α rhythm through triglyceride accumulation in macrophages.

Objectives: Vascular diseases are often caused by the interaction between macrophages and vascular smooth muscle cells (VSMCs). This study aims to elucidate whether chronotherapy with rosiglitazone (RSG) can regulate the secretion rhythm of macrophages, thereby controlling the phenotypic switch of VSMCs and clarifying the potential molecular mechanisms, providing a chronotherapeutic approach for the treatment of vascular diseases. Methods: RAW264.7 cells and A7r5 cells were synchronized via a 50 % FBS treatment. M1-type macrophages were induced through Lipopolysaccharide (LPS) exposure. Additionally, siRNA and plasmids targeting PPARγ were transfected into macrophages. The assessment encompassed cell viability, migration, inflammatory factor levels, lipid metabolites, clock gene expression, and relative protein expression. Results: We revealed that, in alignment with core clock genes Bmal1 and CLOCK, RSG administration at ZT2 advanced the phase of TNF-α release rhythm, while ZT12 administration shifted it backward. Incubation with TNF-α at ZT2 significantly promoted the phenotype switch of VSMCs. This effect diminished when incubated at ZT12, implicating the involvement of the clock-MAPK pathway in VSMCs. Furthermore, RSG administration at ZT2 advanced the phases of PPARγ and Bmal1 genes, whereas ZT12 administration shifted them backward. Additionally, PPARγ overexpression significantly induced triglyceride (TG) accumulation in macrophages. Exogenous TG upregulated Bmal1 and CLOCK gene expression in macrophages and significantly increased TNF-α release. Conclusion: Chronotherapy involving RSG induces TG accumulation within macrophages, resulting in alterations in circadian gene rhythms. These changes, in turn, modulate the phase of rhythmic TNF-α release and play a regulatory role in VSMCs phenotype switch. Our study establishes a theoretical foundation for chronotherapy of PPARγ agonists.

Chrono-Endocrinology in Clinical Practice: A Journey from Pathophysiological to Therapeutic Aspects.

This review was aimed at collecting the knowledge on the pathophysiological and clinical aspects of endocrine rhythms and their implications in clinical practice, derived from the published literature and from some personal experiences on this topic. We chose to review, according to the PRISMA guidelines, the results of original and observational studies, reviews, meta-analyses and case reports published up to March 2024. Thus, after summarizing the general aspects of biological rhythms, we will describe the characteristics of several endocrine rhythms and the consequences of their disruption, paying particular attention to the implications in clinical practice. Rhythmic endocrine secretions, like other physiological rhythms, are genetically determined and regulated by a central hypothalamic CLOCK located in the suprachiasmatic nucleus, which links the timing of the rhythms to independent clocks, in a hierarchical organization for the regulation of physiology and behavior. However, some environmental factors, such as daily cycles of light/darkness, sleep/wake, and timing of food intake, may influence the rhythm characteristics. Endocrine rhythms are involved in important physiological processes and their disruption may cause several disorders and also cancer. Thus, it is very important to prevent disruptions of endocrine rhythms and to restore a previously altered rhythm by an early corrective chronotherapy.

Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8+ T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care.

Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis.

Circadian disruption predicts poor cancer prognosis, yet how circadian disruption is sensed in sleep-deficiency (SD)-enhanced tumorigenesis remains obscure. Here, we show fatty acid oxidation (FAO) as a circadian sensor relaying from clock disruption to oncogenic metabolic signal in SD-enhanced lung tumorigenesis. Both unbiased transcriptomic and metabolomic analyses reveal that FAO senses SD-induced circadian disruption, as illustrated by continuously increased palmitoyl-coenzyme A (PA-CoA) catalyzed by long-chain fatty acyl-CoA synthetase 1 (ACSL1). Mechanistically, SD-dysregulated CLOCK hypertransactivates ACSL1 to produce PA-CoA, which facilitates CLOCK-Cys194 S-palmitoylation in a ZDHHC5-dependent manner. This positive transcription-palmitoylation feedback loop prevents ubiquitin-proteasomal degradation of CLOCK, causing FAO-sensed circadian disruption to maintain SD-enhanced cancer stemness. Intriguingly, timed ß-endorphin resets rhythmic Clock and Acsl1 expression to alleviate SD-enhanced tumorigenesis. Sleep quality and serum ß-endorphin are negatively associated with both cancer development and CLOCK/ACSL1 expression in patients with cancer, suggesting dawn-supplemented ß-endorphin as a potential chronotherapeutic strategy for SD-related cancer.

Association between endocrine adjuvant therapy intake timing and disease-free survival in patients with high-risk early breast cancer: results of a sub-study of the UCBG- UNIRAD trial.

BACKGROUND: Circadian rhythms regulate cellular physiology and could influence the efficacy of endocrine therapy (ET) in breast cancer (BC). We prospectively tested this hypothesis within the UNIRAD adjuvant phase III trial (NCT01805271). METHODS: 1278 patients with high-risk hormonal receptor positive (HR+)/HER2 negative (HER2-) primary BC were randomly assigned to adjuvant ET with placebo or everolimus. Patients prospectively reported in a diary the daily timing of ET intake among four 6-h slots (06:00-11:59 (morning), 12:00-17:59 (afternoon), 18:00-23:59 (evening), or 24:00-05:59 (nighttime). The association between ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial and the results of this observational study are reported here. FINDINGS: ET timing was recorded by 855 patients (67.2%). Patients declaring morning (n = 465, 54.4%) or afternoon (n = 45, 5.4%) ET intake were older than those declaring evening (n = 339, 39.6%) or nighttime (n = 5, 0.6%) intake. With a median follow-up of 46.7 months, 118 patients had a local (n = 30) or metastasis relapse (n = 84), and 41 patients died. ET intake timing was not associated with DFS in the whole population (HR = 0.77, 95% CI [0.53-1.12]). The association between ET intake timing and DFS according to the stratification factors revealed interactions with ET agent (tamoxifen versus Aromatase inhibitors (AI) with an increased DFS in the group of evening/nighttime versus morning/afternoon tamoxifen intake (HR = 0.43, 95% CI [0.22-0.85]), while no association was found for AI intake (HR = 1.07, 95% CI [0.68-1.69]). The interaction between ET intake timing and ET agent remained in multivariable analysis (HR = 0.38 [0.16-0.91]). INTERPRETATION: Tamoxifen intake in the evening/nighttime could be recommended in patients with high-risk HR+/HER2- BC while awaiting for results from further ET timing studies. FUNDING: UNIRAD was Supported by a grant from the French Ministry of Health PHRC 2012 and received funding from La Ligue contre le Cancer, Cancer Research-UK, Myriad Genetics, and Novartis.