
==== Front
J Cancer Res Clin Oncol
J Cancer Res Clin Oncol
Journal of Cancer Research and Clinical Oncology
0171-5216
1432-1335
Springer Berlin Heidelberg Berlin/Heidelberg

39266868
5917
10.1007/s00432-024-05917-w
Review
Circadian rhythms and breast cancer: from molecular level to therapeutic advancements
Li Dou-Dou 1
Zhou Teng 2
Gao Jing 1
Wu Guan-Lin wugl@sumhs.edu.cn

1
Yang Guang-Rui yanggr@sumhs.edu.cn

1
1 https://ror.org/03ns6aq57 grid.507037.6 0000 0004 1764 1277 School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China
2 grid.8547.e 0000 0001 0125 2443 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
12 9 2024
12 9 2024
2024
150 9 41925 6 2024
5 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00432-024-05917-w.

Keywords

Circadian rhythms
Breast cancer
Circadian gene regulation
Tumor microenvironment
Chronotherapy
issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Breast cancer is the most frequently diagnosed malignancy among female worldwide and is a heterogeneous multifactorial disease that attributes to complex interactions between genetic and environmental factors (Siegel et al. 2023; Nolan et al. 2023). Intriguingly, the incidence of breast cancer has increased significantly in developed countries in Europe and the United States compared to developing countries (Sung, et al. 2020). Moreover, a remarkable observation reveals that risk for breast cancer is significantly higher among individuals working nightshifts (Stevens et al. 2014; Carcinogenicity of night shift work 2019; Manouchehri et al. 2021). The above phenomena indicate that the current fast-paced lifestyle may influence the occurrence and progression of breast cancer, one of the possibilities is the disturbance of our internal biological clock, known as circadian rhythms (D'Cunha et al. 2023; Kochan and Kovalchuk 2016).

The circadian rhythm is an adaptive response of organisms to periodic changes in the environment, which reflects the internal rhythm of bodily life activities includes rhythms of different time periods such as days and year (Halberg 1959). The biological clock commonly refers to the circadian rhythm with a period of about 24 h, which is widely present in plants and animals, and can be observed in organisms ranging from photosynthetic prokaryotes to higher eukaryotes, as well as some bacteria and cells cultured in vitro also exhibit this rhythmicity (Balsalobre et al. 1998; Dunlap 1999). In most organs of mammals, there is a circadian rhythm with the regulatory center located in the suprachiasmatic nucleus (SCN) of the hypothalamus, where the information on changes in light signals received by the eyes and optic nerves is processed and transmitted to various tissues, thereby synchronously regulating the biological clock in various tissues (Challet et al. 2003). In addition to the main external stimulus of the daily light and dark cycle, the circadian rhythm may also be influenced by environmental factors (temperature, intensity of light), social behaviors (such as exposure to artificial light, shift work, traveling by plane, irregular sleep patterns, and dietary arrangements), and pre-existing pathological conditions (Fagiani et al. 2022). Due to the crucial role of the biological clock in controlling the physiological functions of almost all tissues, in addition to serving as a generator of circadian rhythms, such as regulating various intracellular signaling pathways, angiogenesis, metabolism and redox homeostasis, inflammation, and immune responses (Fagiani et al. 2022), long-term disturbances in the biological clock caused by external stimuli can lead to the occurrence of various diseases, such as circadian sleep disorders (such as insomnia, time difference), cancer, obesity, arthritis, atherosclerosis and emotional disorders, and ultimately affect life span (Yang et al. 2013).

The occurrence and progression of tumors have been confirmed to be related to the disruption of the human circadian rhythm, including endometrial cance (Shih et al. 2006), prostate cance (Flynn-Evans et al. 2013), lung cancer (Hu et al. 2009), colon cancer (Mostafaie et al. 2009), hepatocellular carcinoma (Lin et al. 2008), and ovarian cancer (Tokunaga et al. 2008). Typically, the relationship between circadian rhythm disorder and breast cancer was first reported in the 1960s, the circadian rhythm disorder will increase the possibility of breast tumor development, and the circadian rhythm gene may play the role of tumor inhibitor (Hamilton 1969). In the past few decades, studies have shown that changes in circadian rhythms can also accelerate the proliferation of breast epithelial stem cells, induce breast development, and increase the formation of spontaneous breast tumors in mammals (Aubert et al. 1980; Mhatre et al. 1984). In addition, the rhythmic control of cells is believed to affect breast cancer treatment: the efficacy and toxicity of chemotherapy and radiotherapy have been shown to depend on the administration time (Roche et al. 2014; Dallmann et al. 2016). Identifying the relationship between circadian rhythm and breast cancer could help optimize existing treatments and open up entirely new avenues of therapies.

In this review, we comprehensively summarize the effects of circadian rhythm on the occurrence and development of breast cancer from the aspects of biological rhythm, circadian genes regulation, tumor microenvironment, single nucleotide diversity. In addition, we discuss strategies of manipulating the circadian rhythm in treatment of breast cancer.

Roles of circadian rhythm in breast cancer

Circadian rhythm disorders can lead to immunosuppression (Labrecque and Cermakian 2015) and metabolic changes (Arble et al. 2010), which can lead to various health problems, including cardiovascular disease (Morris et al. 2016), obesity (Shi et al. 2013), diabetes (Gale et al. 2011), and cancer (Savvidis and Koutsilieris 2012). Therefore, the International Agency for Research on Cancer categorizes "shift work involving circadian rhythm disorders" as "potential carcinogens to humans" (Baan et al. 2009). What’more, Normal mammary cells in our bodies have a functional clock whose disruption leads to abnormal growth of mammary cells, thereby leading to breast cancer (Verlande and Masri 2019). Interruptions in sleep (night shift, shift work as well as jet lag) and lifestyle habits (diet as well as exercise) have now been found to affect breast cell biological clock function, leading to metabolic disruption, which in turn promotes breast cancer progression (Kiehn et al. 2017).

In the past 15 years, the number of human studies investigating the relationship between night shift and shift work and BC has more than tripled (Hansen 2017). Additionally, Numerous epidemiological studies provide sufficient evidence to support the association between shift work and cancer risk (Wegrzyn et al. 2017; Ijaz et al. 2013). What’s more, night shift workers have a slightly increased risk of breast cancer, and among people who live according to a circadian rhythm (more activity in the morning and less active in the evening) have a lower risk of developing breast cancer (Muscogiuri et al. 2023; Papantoniou et al. 2017). Manouchehri et al. recently conducted a systematic review and meta-analysis, which showed that both short-term and long-term night shift workers have an increased risk of breast cancer. Furthermore, a population-based case–control study in France (CECILE study) collected lifetime occupational history data to investigate the impact of night shifts on breast cancer risk. The results showed that night shifts increase the risk of breast cancer, especially for women who started working night shifts before their first full-term pregnancy. These findings emphasize that women may be particularly sensitive to the potential carcinogenic effects of circadian rhythm disruption during the phase of incomplete differentiation of breast cells prior to their first delivery (Menegaux et al. 2013).

In addition to night shifts and shift work, sleep disorders caused by crossing multiple time zones in a short period of time (Choy and Salbu 2011), also known as jet lag, is another environmental factor related to changes in circadian rhythm and high cancer incidence (Kettner et al. 2016). An early study showed that compared with ordinary women (57.4/10000) (Pukkala et al. 1995), the incidence rate of cancer among flight attendants (81.2/10000) was significantly higher. This is because excessive exposure to light during normal sleep time can disrupt sleep rhythm, leading to dysregulation of melatonin and ultimately triggering cancer (Kojo et al. 2005).

The influence of diet and exercise on circadian rhythm would also affect the progress of breast cancer. A population-based case–control study conducted in Spain from 2008 to 2013 found that compared with subjects who fell asleep immediately after dinner, subjects who slept two or more hours after dinner had a 20% reduced risk of breast cancer (adjusted Odds Ratio [OR] 50.80, 95% CI 0.67–0.96) (Kogevinas et al. 2018). Catherine et al. revealed that prolonging the time of fasting at night may be a simple non drug strategy to reduce the risk of recurrence of breast cancer (Marinac et al. 2016), because more frequent eating, reducing energy intake at night and prolonging the time of fasting at night may reduce systemic inflammation, thereby reducing the risk of cancer (Marinac et al. 2015). A population-based case–control study (MCC Spain) found that for breast cancer (OR = 0.74, 95% CI = 0.48–1.15), compared with no physical activity, early morning (8–10 a.m.) activity was associated with protection, while late morning, afternoon and night activities had no effect on breast cancer (Weitzer et al. 2021).

Circadian genes affect breast cancer

Circadian rhythm is orchestrated by a set of genes called clock genes, governing the cycling expression of downstream genes, referred as “clock-controlled genes” (CCGs), resulting in daily oscillations of proteins synthesis (Darlington et al. 1998). A tightly regulated network, driven by genes such as circadian locomotor output cycles kaput (CLOCK)/Npas2, brain and muscle ARNT-like protein 1 (BMAL1), period (PER), and cryptochrome (CRY), is established through interwoven feedback and feedforward loops (Chen and Yang 2014). In one of the regulatory circuits, the transcription activators BMAL1 and CLOCK team up to form CLOCK/BMAL1 heterodimers in the nucleus, marking the commencement of the circadian rhythm. They activate the expression of PER and CRY genes by binding to the E-box promoter sequences. In the cytoplasm, PER and CRY proteins bind together to form complexes that move into the nucleus and inhibit the activity of the CLOCK/BMAL1 heterodimers, thus halting the transcription of PER and CRY genes. This leads to the initiation of a new transcription cycle by BMAL-1/CLOCK, thereby closing the loop. In another regulatory cycle, the expression of the BMAL1 gene is controlled through CLOCK/BMAL1 heterodimer formation in the nucleus. These heterodimers bind to the E-box promoter sequences of genes that encode the retinoic acid-related orphan nuclear receptors (ROR) and Rev-erbα; The ROR and Rev-erbα proteins then vie for the ROR element (RORE) in the BMAL1 promoter, either activating or repressing BMAL1 expression, respectively (Kochan and Kovalchuk 2015).

Considering the intricate mechanisms by which circadian rhythms are regulated, it’s imperative to explore how disruptions in this finely tuned system might contribute to disease states, notably breast cancer. The relationship between breast cancer and key circadian regulators such as CLOCK, BMAL1, the PER gene family, and CRY is particularly compelling. Therefore, it is essential to explore how alterations in these circadian regulators affect the development and progression of breast cancer.

Breast cancer and CLOCK

CLOCK, identified as a significant factor in the development of tumors, particularly breast cancer, demonstrates variable expression levels between healthy and cancerous breast tissues. Studies have shown that the presence of CLOCK is more pronounced in breast cancer tissues, indicating its role in tumor biology. The functional inhibition of CLOCK, through knockout techniques, leads to a reduction in breast cancer cell proliferation and lowers the expression of various genes that are implicated in the progression and onset of metastasis in breast cancer, such as BDKRB2, SP100, and CCL5. Interestingly, an increase in methylation within the promoter region of the CLOCK gene correlates with a decreased risk of developing breast cancer, suggesting a potential epigenetic mechanism for cancer risk modulation (Xiao et al. 2014).

Further investigation into the circadian rhythm's influence on breast cancer has revealed that the PER1 gene undergoes significant hypomethylation in estrogen receptor-positive/progesterone receptor-positive (ER + /PR +) breast cancer tissues (Li et al. 2010). This alteration in methylation status might disrupt the normal circadian function, contributing to tumorigenesis. Moreover, abnormal expression levels of the PER1, 2, and 3 proteins in breast cancer tissues, as opposed to their non-cancerous counterparts, have been documented (Chen et al. 2005). These variations in expression patterns could stem from changes in the methylation of the PER gene promoters, highlighting the complex interplay between circadian rhythm genes and cancer development.

These findings underscore the intricate relationship between circadian rhythm disruptions, particularly involving CLOCK and PER genes, and breast cancer progression. Understanding these dynamics offers a window into the molecular underpinnings of breast cancer, providing potential targets for therapeutic intervention aimed at mitigating tumor growth and spread by addressing circadian rhythm abnormalities.

Breast cancer and PER

PER family in clock genes are the most studied gene population related to breast cancer. Recent studies have shown that overexpression of PER1 and PER2 significantly inhibits cell growth and promotes apoptosis (Gery et al. 2007; Xiang et al. 2008). On the one hand, PER1 plays a role in apoptosis in human cancer cells, with its down-regulation stopping apoptosis and its overexpression increasing DNA damage-induced apoptosis (Gery et al. 2006). On the other hand, the PER2 gene plays a critical role in combatting luminal breast cancer by connecting the circadian oscillator system with the function of estrogen receptor α (ERα), functioning as a tumor suppressor. Specifically, researchers have observed that the loss of rhythmic oscillations of PER2 mRNA is a phenomenon unique to ERα-positive breast cancer cells, whereas ERα-negative cells still exhibit some rhythmic activity (Rossetti et al. 2012a, b). In mammary cells, PER2 can be induced by estradiol (E2), which can be utilized to reduce ERα activation (Haus and Smolensky 2013). Given that activation of ER by E2 contributes to the formation of DNA adducts, cell proliferation, and genotoxic byproducts, the role of PER2 in reducing ERα activation emerges as a mechanism with potential anticancer effects (Parl et al. 2009). Also, PER2 is associated with the EMT pathway, and PER2 in normal breast tissues represses the expression of EMT genes (Twist1, Slug, and Snail) by recruiting a repressor complex to the promoter regions of these genes through interaction with OCT1. Thus, PER2 deficiency promotes breast cancer cell invasion and metastasis (Kelleher et al. 2014) (Figs. 1, 2, 3).Fig. 1 Transcription–translation feedback loops of mammalian circadian clock. The transcription factors CLOCK–BMAL1 heterodimer induce the expression of Period (PER) and Cryptochrome (CRY) proteins via binding to E-box in their promoters. Accordingly, accumulate PER and CRY proteins dimerize and translocate from the cytoplasm to the nucleus to suppress BMAL1-CLOCK transcriptional activity. Furthermore, CLOCK–BMAL1 heterodimer also activates transcription of REV-ERBα and REV-ERBβ (REV-ERBα/β), which binds to the retinoid-related orphan receptors (RORα/β/γ) elements in the BMAL1 promoter, suppressing BMAL1 transcription. REV-ERBα/β also oppose the expression of D-box binding protein (DBP), which activates transcription from D-box-containing genes including RORα/β/γ. REV-ERB and ROR target gene NFIL3 inhibit D-box dependent transcription

Fig. 2 Roles of circadian rhythm in breast cancer. The central circadian pacemaker is situated within the suprachiasmatic nuclei (SCN), where it receives time-of-day information from light, and governs peripheral clocks throughout the timing of food intake and exercise. Normal mammary cells have a functional clock whose disruption leads to abnormal growth of mammary cells, thereby leading to breast cancer. Circadian rhythm-related risk factors that promote breast cancer are distinguished by colour. Night shifts, shift work and jet lag, are environmental factor related to changes in circadian rhythm, which promote breast cancer incidence. Besides, compared with subjects who fell asleep immediately after dinner, subjects who slept two or more hours after dinner had a 20% reduced risk of breast cancer. Conversely, compared with no physical activity, early morning (8–10 a.m.) activity was associated with protection against breast cancer

Fig. 3 Breast Tumor Microenvironment and Circadian Rhythms. The role of Circadian rhythm disorder (CRD) in the breast tumor microenvironment mainly includes regulating the autonomic response of tumor cells and stimulating the secretion of inflammatory cytokines, immune surveillance through immune cell infiltration and activation of tumor-associated fibroblasts, promoting the occurrence of  epithelial-mesenchymal transition (EMT)

Breast cancer and CRY

Although both CRY genes may be implicated in the development of breast cancer, the majority of research to date suggests a more prominent role for CRY2. Studies of the CRY2 gene in the development of breast cancer have revealed its importance as a potential tumor suppressor, particularly in non-luminal breast cancers. By identifying single nucleotide polymorphisms (SNPs) associated with the CRY2 gene, studies have pointed to the possibility that these genetic variants may increase the risk of breast cancer and that CRY2 is expressed at higher levels in non-luminal breast cancers. Knockdown exPERiments of CRY2 in cell model studies, particularly in MCF-7 breast cancer cells, demonstrated that CRY2 has a significant impact on the regulation of key processes such as cell differentiation, proliferation, motility, angiogenesis, and apoptosis, further emphasizing its potential role in inhibiting breast cancer. These findings not only provide new insights into the molecular mechanisms of breast cancer, but also offer potential targets for future breast cancer treatment strategies.

Breast cancer and CLOCK/BMAL1 heterodimer

CLOCK and BMAL1 genes play a dual role in breast cancer development, regulating cell cycle genes associated with breast cancer progression through their constitutive CLOCK/BMAL1 heterodimer (Haus and Smolensky 2013). This regulation includes both mechanisms that promote breast cancer growth (Fu et al. 2002; Chen-Goodspeed and Lee 2007; Matsuo et al. 2003). such as increased DNA repair through activation of the WEE1 G2 checkpoint kinase, a nuclear kinase whose overexpression is ubiquitous in breast cancer cells and which aids in the transition from G2 phase to mitosis, and increased DNA repair in breast cancer cells before they enter mitosis, through the inhibition of CDK1 protein activity (Vriend et al. 1836; Parker and Piwnica-Worms 1992). It also includes anti-tumor effects, such as reducing breast cancer proliferation and inhibiting breast cancer apoptosis by inhibiting c-MYC gene expression. c-Myc is a regulatory gene whose overexpression promotes cell proliferation by increasing cyclin activity and reduces apoptosis by decreasing Bcl-2 activity, which ultimately leads to hyperplasia and breast cancer development. This complex regulatory mechanism highlights the potential value of CLOCK and BMAL1 in maintaining cell cycle homeostasis and its role in breast cancer treatment strategies (Table 1).Table 1 Significant link between circadian genes polymorphism and breast cancer risk

Circadian gene	db SNP	Study population	Phenotype	References	
CLOCK	rs7698022	USA; mixed ethnicity	Increased risk	91	
	rs11133391	USA; mixed ethnicity	Reduced risk	91	
	rs11932595	USA; mixed ethnicity	Increased risk	91	
		France; European origin	Reduced risk	95	
	rs1048004	USA; mixed ethnicity	Increased risk	91	
	rs3805151	China; Han Chinese	Increased risk	92	
	rs10462028	Germany; European origin	Increased risk	93	
	rs3749474	Norway; European origin	Reduced risk	94, 96	
BMAL1	rs3816358	Germany; European origin	Reduced risk	93	
	rs2278749	Norway; European origin	Reduced risk	94	
	rs3816360	Canada; mixed ethnicity	Increased risk	97	
NPAS2	rs23051560	USA; mixed ethnicity	Increased risk	99	
	rs356642	Canada; mixed ethnicity	Reduced risk	97,100	
CRY1	rs11113179	Canada; mixed ethnicity	Increased risk	97	
CRY2	rs11038689	USA; mixed ethnicity	Reduced risk	101	
	rs7123390	USA; mixed ethnicity	Reduced risk	101	
	rs1401417	China; Han Chinese	Reduced risk	92	
	rs11605924	USA; mixed ethnicity	Increased risk	101	
PER2	rs934945	China; Han Chinese	Increased risk	92	
PER3	rs57875989	USA; mixed ethnicity	Increased risk	102	
TIMELESS	rs7302060	USA; mixed ethnicity	Reduced risk	103	
	rs2291738	USA; mixed ethnicity	Reduced risk	103	

Breast cancer and other circadian rhythm-related genes

In addition to the roles of CLOCK, PER, CRY, and CLOCK/BMAL1 heterodimers in breast cancer development, another key regulatory pathway, the Nrf2/ARE pathway, which is regulated by circadian rhythms, plays a critical role in managing oxidative stress and also exhibits dual function—depending on different factors, it may either exhibit anti-tumor effects or promote tumor progression (Bevinakoppamath et al. 2021). Studies have shown that the proliferation and migration of breast cancer cells such as MDA-MB-231 and MCF-7 are significantly reduced following Nrf2 gene silencing, suggesting a role for Nrf2 in cancer progression through mechanisms that regulate RhoA and estrogen-related receptor alpha (ERR1). In contrast, attenuated Nrf2 signaling was associated with increased cancer cell proliferation, highlighting the potential therapeutic implications of targeting the Nrf2 pathway in breast cancer therapy. In addition, the role of Nrf2 in breast cancer metastasis, through its effects on cell migration and invasion and regulation of MMP-2 and MMP-9 enzyme activities, further emphasizes its complex functions in cancer biology. Some studies have explored the role of circadian genes in maintaining breast cancer stem cell (CSC) identity, with a particular focus on the CLOCK gene (Ogino et al. 2021).

In ALDH-positive 4T1 breast cancer cells, CLOCK mRNA and protein expression levels were downregulated, and lentiviral transduction of CLOCK expression reduced the malignant potential of these cells. The number of ALDH-positive population in 4T1 cells was reduced by increasing CLOCK expression. The detoxification capacity of ALDH protects stem cells from oxidative damage and is an important factor for their longevity. Our findings suggest a possible strategy to overcome the malignancy of BCSCs through miRNA-mediated post-transcriptional regulation targeting the circadian component CLOCK.

In conclusion, exploring the link between circadian genes and breast cancer reveals the potential for therapeutic innovation. As our understanding of this complex interaction grows, future research promises to develop more precise treatment strategies. This will not only allow for optimizing the timing of drug treatments based on patient-specific circadian rhythms, but may also allow for direct modulation of key circadian genes that influence tumor growth through gene therapy. Such advances represent an important step forward in improving the efficiency of treatments and reducing side effects, while at the same time offering more personalized treatment options and a brighter future for breast cancer patients.

Breast tumor microenvironment and circadian rhythms

Several studies have elucidated the tumor microenvironment is indispensable for the initiation and progression of breast cancer (Ogino et al. 2021). Tumor microenvironment provides a niche for residing and interacting cancer cells with their surrounding fibroblasts, immune cells as well as extracellular matrix, to predisposes cancer cells to metastasis and escape the cytotoxic effects of chemoradiotherapy (Mehraj et al. 2021; Braman et al. 2022; Mao et al. 2013). Circadian rhythm disorder (CRD) prone to form a tumor microenvironment with inflammatory infiltration, immunosuppression as well as epithelial-mesenchymal transition (EMT) (Hadadi and Acloque 2021). During the last decades, EMT, which is characterized by the loss of cell-to-cell adhesion, increased cellular plasticity, and development of a mesenchymal phenotype, has become the spotlight of progression and metastasis in solid tumors including breast cancer (Dongre and Weinberg 2019; Nieto et al. 2016). Furthermore, the inflammatory infiltration of breast cancer cells can stimulate the secretion of cytokines such as IL-6, TGF-β and SDF-1 by the tumor microenvironment, then facilitate the occurrence of EMT (Orimo et al. 2005; Müller et al. 2001; Weng et al. 2019; Xie et al. 2022).

The core transcription factors of the circadian rhythms can regulate the expression of EMT-related molecular markers. Downregulation of circadian clock gene PER2 promotes breast tumor malignancy by enhancing invasion and activating EMT gene expression (Hwang-Verslues et al. 2013). Moreover, hypoxia down-regulates PER2 posttranslationally to de-repress EMT gene expression (Hwang-Verslues et al. 2013). Conversely, circadian protein BMAL1 promotes breast cancer cell invasion and metastasis by activating the NF-κB signaling pathway and up-regulating matrix metalloproteinase 9 expression (Wang et al. 2019). Several studies indicate that disruption of the circadian nocturnal melatonin promotes tumor aerobic glycolysis, critical cell-signaling pathways relevant to the proliferation, metabolism, metastasis and EMT of breast cancer, resulting in resistance to hormone therapy and chemotherapy (Kong et al. 2020; Maroufi et al. 2020; Mao et al. 2016; Hill et al. 2015). Furthermore, analysis of EMT-related gene expression of primary breast tumors under CRD conditions, the elevated EMT inducers: Zeb2, Foxc2 and Inhba also have properties that promote stem cell formation and metastasis (Mani et al. 2008). Collectively, CRD increases the properties of stem cells through modulating EMT induction, contributes to the generation of an immunosuppressive breast tumor microenvironment.

CRD caused by environmental stress like long night shift and chronic jet lag also stimulates the secretion of inflammatory cytokines, enhances the stemness and tumor-initiating potential of tumor cells and creates an immunosuppressive shift in the tumor microenvironment. CRD has a profound impact on tumor immunity through regulating the cytokine–chemokine network. CRD attenuates immune infiltration to tumor sites potentially by disrupting the diurnal trafficking of leukocytes and consequently reducing the daily total number of these cells in the circulation (Zhao et al. 2017). A recent study illustrated that CRD induces a protumorigenic switch of the tumor immune microenvironment, primarily driven by alterations in the CXCL5-CXCR2 axis (Hadadi et al. 2020). Furthermore, CXCR2 and its ligands (CXCL1, CXCL2, CXCL5, CXCL7 and CXCL8) have the inseparable relation with the occurrence and metastasis of breast cancer (Cheng et al. 1871). Moreover, up-regulation of the CXCL12-CXCR4 axis was observed in chronic jet lag (JL) mice, whose role in immunosuppression and breast cancer metastasis has been widely demonstrated. In JL mice model, researchers observed the enrichment of stem-cell populations in primary tumors. In addition, they found varying degrees of increase in stem-cell properties and tumorigenic potential in JL cancer cells. mammary epithelial cells derived from CLOCK 19 mutant mice showed diminished mammosphere-formation capacity. Particularly, the stemness of mammary epithelial cells oscillates diurnally was observed. A recently study demonstrated that high CD8 + T cell infiltration was associated with low-circadian rhythms-protein expression. Importantly, patients with low circadian rhythm signature were more likely to benefit from immune checkpoint blockade treatment, possibly due to their incremental immune checkpoint expression, higher tumor mutation burden, and higher proportion of “hot” immunophenotype. All above illustrate that chemokine/chemokine-receptor signaling as a possible mechanism behind CRD-related increased stem-cell properties and attenuated anti-tumor immunity.

Circadian gene polymorphisms and breast cancer

In addition to light at night (LAN) exposure, shift work, genetic predispositions and tumor microenvironment, dysfunction of circadian clock genes is largely influenced by circadian genetic polymorphism, which provide valuable linkage for the susceptibility to breast cancer. Consequently, multiple epigenetic articles have intensively laid emphasis on estimating the value of the polymorphisms in core circadian genes and signaling pathways.

CLOCK is the first corroborative mammalian circadian clock gene, which been identified as a critical regulator of breast cancer occurrence and progression. A study from Yale University reported vital interplay between single nucleotide polymorphisms (SNPs) correlative to CLOCK and breast cancer risk, with apparent effect modification by estrogen receptor/progesterone receptor status. Among the nine SNPs investigated, four SNPs were found to be involved in breast cancer risk assuming a dominant model, including three tagging SNPs (rs7698022, rs11133391, and rs11932595) and one 3′UTR SNP (rs1048004) (Hoffman et al. 2010). Moreover, CLOCK gene variants were of particular significance for ER/PR- breast cancer is especially notable, such tumors were characterized by early onset, malignancy aggressiveness, strong invasion, high risk of postoperative recurrence and metastasis, high probability of visceral and brain metastasis, poor clinical prognosis and do not benefit from endocrine therapy. In another Chinese population study, researchers confirmed that carriers of the CLOCK (rs3805151) CT and combined CT + TT genotypes had a significantly higher risk of breast cancer than carriers of the CC genotype (Dai et al. 2011). GENICA is a population-based case–control study on breast cancer conducted in the Greater Region of Bonn. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (Rabstein et al. 2014). However, in the main effects analysis, TT carriers of CLOCK rs3749474 had reduced risk of breast cancer (Zienolddiny et al. 2013). Among a population-based case–control study in France, Stratification by menopausal status indicated that breast cancer in postmenopausal women was associated with rs11932595 in CLOCK, with P values at the limit of statistical significance (Truong et al. 2014). No association was apparent in premenopausal women. Beyond that, A recent meta-analysis showed that compared with T/T types of rs3749474 in CLOCK, T/C and C/C types of rs3749474 were associated with lower risk of breast cancer (Shi et al. 2023).

As an important core clock protein, SNPs in BMAL1 is closely related to breast tumorigenesis. For combined heterozygotes and rare homozygotes, a reduced breast cancer risk was observed for rs3816358 in gene BMAL193. Furthermore, a nested case–control study conducted among Norwegian nurses showed that TT carriers of BMAL1 rs2278749 had reduced risk of breast cancer (Zienolddiny et al. 2013). Another case–control study was conducted to identify risk factors for breast cancer, PER mutation analysis proved that rs3816360 in BMAL1 display significant associations with enhanced risk of breast cancer (Grundy et al. 2013).

NPAS2 as another circadian rhythm gene, has received widespread attention due to its functions in the occurrence and development of multiple diseases, especially tumorigenesis. As early as 2008, a case–control study conducted in the USA confirmed that women carrying heterozygous Ala394Thr genotype had a higher risk of breast cancer than those carrying the Ala394Ala genotype (Zhu et al. 2008). Another study analyzed the correlations between values of sleep quality and genetic variants in 26 circadian clock genes in women with breast cancer. They found that rs23051560 in NPAS2 was most intimately relate to breast cancer risk. Moreover, patients carrying homozygous AA who worked ≥ 24 months of shift-work had a 2.83-fold increased risk of breast cancer compared with breast cancer patients who worked < 24 months of shift-work (Monsees et al. 2012). Besides, the minor allele of NPAS2 rs356642 was correlated with a reduced risk of breast cancer in women in both the Canadian study and the GWAS study (Grundy et al. 2013; Li et al. 2011).

Specific CRYs, PERs and TIMELESS are vital component of the negative limb of the circadian transcription-translation feedback loop, which draw a similarly inconsistent picture in breast cancer susceptibility. A population-based case–control study among Chinese population demonstrated that carriers of the CRY1 GT genotype had a decreased risk of breast cancer. However, rs11113179 in CRY1 was closely linked with increased breast cancer risk in a Canadian study (Grundy et al. 2013). Besides, a lower risk of breast cancer was observed in carriers of the CRY2 CC genotype who were ER-positive than in those who were ER-negative. When stratified by the CLOCK genotype, patients with CRY2 CC genotypes had significantly lower cancer risk than those with the GG genotype (Hoffman, et al. 2010). Three SNPs (rs11038689, rs7123390, and rs1401417) in CRY2 demon-strates significant correlations with post-menopausal breast cancer risk, which menopausal status was a potential modifier (Dai et al. 2011). Surprisingly, four SNPS (rs11038689, rs11605924, rs7123390, and rs1401417) were strongly relevant for ER and PR negative breast tumorigenesis. Individuals carrying PER2 AA genotypes had an increased cancer risk. PER2 (rs934945) have been associated to breast cancer risk in a Chinese population (Dai et al. 2011). A case–control study in USA revealed that rs57875989 in PER3 was associated with an increased risk of breast cancer in patients with perimenopause (Zhu et al. 2005). Beyond that, two tagging SNPs in the TIMELESS gene were detected to be significant associated with breast cancer. The presence of the C allele of rs7302060 may reduce the risk of breast cancer. Further analysis revealed that the G/G genotype of rs2291738 and the C/C genotype of rs7302060 was related to a lower risk of breast cancer among ER + breast cancer patients (Fu et al. 2012).

These findings highlight a distinctly important role of polymorphisms related with the circadian clock in breast cancer and may facilitate development of new targeted intervention therapies to improve the outcome of breast cancer patients.

Circadian Rhythms and breast cancer therapy

In recent years, strategies of manipulating the circadian rhythm have been applied to the treatment of breast cancer by regulating the activity of circadian clock molecules and related signaling pathways, enhancing the intrinsic circadian rhythm of the tumor and optimizing the delivery of antitumor agents according to the host circadian rhythm (Kojetin and Burris 2014; Wang et al. 2015).

The influence of circadian rhythm on treatment effectiveness has become increasingly prominent. Chronotherapy which is the treatment administered based on the circadian rhythm, has been conducted in numerous previous and ongoing clinical trials in cancer management due to its accessible, cost free and better healthy tissue protection. Researchers observed a significant increase in tumor volumes after cisplatin treatment in mice with circadian disorders compared to normal clock conditions, a reduced tumor growth rate in mice treated at Zeitgebertime (ZT)10 compared to ZT22 and untreated cohorts under normal clock conditions, suggesting that the effectiveness of cisplatin in breast cancer therapy is time-dependent in the presence of the circadian clock (Koritala et al. 2022). Recently, a randomized, multicentre clinical study investigating the optimum timing (morning vs. evening) of endocrine therapy is being conducted in 247 patients with early stage or locally advanced hormonal receptor positive breast cancer, the trial focuses on the comparative treatment-related toxicity and tolerability, as well as compliance and intrinsically, patients’ quality of life.

As a neurohormone, melatonin participates in a variety of physiological and biochemical processes, including regulating biological rhythms, anti-neoplastic effects and may increase the effectiveness of chemotherapy (Samanta 2022). It is worth noting that melatonin antagonizes the effects of estrogen on the proliferation, invasion and telomerase activity of breast cancer cells, augments the sensitivity of estrogen receptor modulators such as tamoxifen and decreased the expression of estrogen-regulated proteins, proto-oncogenes, and growth factors (Dauchy et al. 2014; Sabzichi, et al. 2016). Melatonin levels can influence the aggregation of estrogen receptors, which inhibits the proliferation of ER-positive breast cancer cells via blocking ERs (Dauchy et al. 2014). In addition to hormone-positive breast cancer, melatonin also plays an integral role in TNBC. Melatonin inhibited TNBC progression through the lnc049808-FUNDC1 pathway and melatonin could be used as a potential therapeutic agent for TNBC (Yang et al. 2021). Furthermore, in postmenopausal breast cancer patients, melatonin exerts anti-aromatase roles via regulating cyclooxygenase (COX) gene activity (Wang et al. 2012). Melatonin can suppress the activation of upstream COX2 related signaling pathways, including ERK1/2, JNK, p38 MAPK, and NF-κB. Down-regulation of COX enzymes reduces the expression of PGE2, which is a tumor promoter generated by COX2 and in charge of cell proliferation, death and angiogenesis (Martínez-Campa et al. 2009). Besides, through reducing the expression and activity of aromatase in luminal breast cancer cells, melatonin inhibits estrogen biosynthesis and enhances drug sensitivity of aminoglutethimide (Martínez-Campa et al. 2005). The radiosensitivity of breast cancer cells by melatonin is mediated through decreased cell proliferation, incremental p53 mRNA levels, the facilitation of cell cycle arrest, downregulated DNA repair (Alonso-González et al. 2016). Interestingly, melatonin has the ability to protect normal tissue from the cytotoxicity accompanied with radiation therapy (Griffin and Marignol 2018). An early study clarified that melatonin inhibits angiogenesis in ER-negative breast cancer via down-regulating VEGFR2 expression (Jardim-Perassi et al. 2016). A recent study further confirmed that melatonin blocks proangiogenic and potentiates antiangiogenic effects induced by docetaxel and vinorelbine enhancing their antitumor effectiveness (González-González 2019). CyclinD1 is overexpressed in the vast majority of breast cancer, and its expression level is closely correlated with negative prognosis. Melatonin has been shown to inhibit cyclin D1 transcription, with favorable effects in hormone-sensitive breast cancer (González-González 2019). A study in vitro confirmed that the combined use of Melatonin and Alpelisib may be more effective in inhibiting breast cancer in women carrying the PIK3CA gene mutation than either treatment alone (Godoy et al. 2023). A newly study proves that melatonin could be utilized in breast cancer therapy via suppression of the PI3K/Akt/mTOR signaling and differential modulation of SIRT1 and NF-κB proteins, facilitating the establishment of apoptotic and autophagic fates in breast cancer cells (Das et al. 2024). Except above roles, melatonin administration may ameliorate sleep quality related to treatments in breast cancer patients as well as combined with standard chemotherapy would derive, at least, a better quality of life for breast cancer patients.

For the last few years, the role of traditional Chinese medicine in the treatment of breast cancer related to circadian rhythms has become increasingly prominent. By virtue of modulating circadian rhythms genes PER2 and BMAL1, nobiletin performs anti-oncogenic effects through preventing cell migration and formation of anchorage independent colonies (Wu et al. 2023; Lellupitiyage Don et al. 2020). Further study highlights that nobiletin enhanced the antitumor efficacy in TNBC via binding to and regulating the promoter region of ROR nuclear receptors, multifunctional transcription factors with vital roles in circadian pathways, as well as suppression of NF-κB signaling (Kim et al. 2022). All above suggest novel preventive and chemotherapeutic strategies against breast cancer.

Poly ADP-Ribose Polymerase1 (PARP1) is involved in multitudinous pathophysi-ological processes such as DNA damage repair, transcriptional regulation, and chromosome remodeling. In a previous report, Zada et al., show that DNA lesions, recognized by PARP-1, accumulate in neurons of zebrafish larvae and promote homeostatic sleep pressure, which suggests that PARP-1 as a novel and unexpected molecular regulator of circadian clock oscillations (Schibler 2021). As the first-in-class PARP inhibitor, the oral PARP inhibitor Olaparib has shown promising activity and clinically meaningful benefit among the patients with metastatic breast cancer and a germline BRCA mutation (Kaufman et al. 2015; Tutt et al. 2010). Intriguingly, a new study identified Olaparib alters circadian clock oscillation by incrementing the amplitude of the clock gene PER3 in breast cancer. Administration of combined PRMT6 and PARP1 inhibitors may obstruct tumor progression by recovering the natural circadian rhythm (Yang, et al. 2023). Thus, Olaparib has potential antitumor effects in high-PRMT6 expression breast cancer.

Conclusions and future perspective

Circadian rhythms are essential for the regulation of multiple physiological processes and behavioral functions in humans. CRD is crucial for the development of a variety of tumors, including breast cancer. our study has elucidated that alterations in external biological rhythm such as the timing of food intake and exercise affect the development of breast cancer. Understanding how clock genes work together provides a direct view of the relationship between genes and breast cancer development, particularly treatment resistance. Chronotherapy, circadian intervention as well as neurohormone that regulating biological rhythms are all part of a new circadian medicine, which will hopefully become a safe and low­cost standard intervention for breast cancer. Researches with novel molecular regulator of circadian clock oscillations warranting further exploration.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 17 KB)

Abbreviations

TNBC Triple-negative breast cancer

ER Negative estrogen receptor

PR Progesterone receptor

VEGF Vascular endothelial growth factor

VEGFR-2 Vascular endothelial growth factor receptor-2

OR Odds ratio

ROR Retinoic acid-related orphan nuclear receptors

CCGs Clock-controlled genes

BMAL1 Brain and muscle ARNT-like protein 1

PER Period

CRY Cryptochrome

ERR1 Estrogen-related receptor alpha

CSC Cancer stem cell

CRD Circadian rhythm disorder

EMT Epithelial-mesenchymal transition

JL Chronic jetlag

LAN Light at night

SNPs Single nucleotide polymorphisms

ZT Zeitgebertime

COX Cyclooxygenase

PARP1 Poly ADP-ribose polymerase1

Author Contribution

Dou-Dou Li and Teng Zhou: Data curation Jing Gao: Investigation Guan-Lin Wu: Methodology Dou-Dou Li and Teng Zhou: Writing – original draft Dou-Dou Li and Teng Zhou and Guang-Rui Yang: Writing – review & editing.

Funding

This study was funded by the National Natural Science Foundation of China (32171165).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dou-Dou Li and Teng Zhou have contributed equally.
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