Mini-reviewCircadian gene variants and breast cancer
Introduction
Apart from the reproductive cycle, lifestyle, genetic predispositions and family history of the disease [1], [2], the origin of breast cancer appears to be linked with circadian gene alterations. Recent findings show that women living in industrialized societies suffer elevated breast cancer risk, with artificial light exposure indicated as a key risk factor. A 30–50% higher risk of breast cancer was attributable to light at night (LAN) exposure in the highest LAN-exposed countries compared to the lowest LAN-exposed regions [3]. Two meta-analyses of epidemiological studies showed that shift work and LAN exposure were associated with slightly elevated breast cancer risk among women, estimated as 19% and 12% increase in cancer risk, respectively [4], [5]. However, recent meta-analysis focused only on prospective studies has indicated that shift work has little or no effect on breast cancer incidence [6]. Although shift work that involves circadian disruption has been classified by the International Agency for Research on Cancer as a probable human carcinogen, group 2A, based on limited evidence of carcinogenicity in humans and mounting evidence of carcinogenicity in experimental animals [7], [8], the role of circadian disruption, specifically in breast cancer development, is still unclear.
The 24-h human sleep–wake rhythm is critical in synchronizing between environmental cues, including light and temperature changes on the one hand, and behavioral and internal states including dietary patterns, body temperature, energy metabolism, hormone secretion, and cell cycles on the other [9]. Thus, circadian rhythm disruption due to shift work and LAN exposure and also additional night shift work-related mechanisms like phase shift, sleep disruption, lifestyle factors (poor quality diets, less physical activity and higher body mass index), and lower vitamin D intake may result in elevated cancer risk [10].
The link between exposure to LAN during shift work and breast cancer risk was based on hypothesis suggesting that suppression of secretion of nocturnal melatonin in the pineal gland might increase the risk of breast cancer [11]. Melatonin might plausibly influence hormone estrogen and estrogen receptor (ER) activities [12], [13], and hence, lead to breast cancer. Currently, it is also believed that exposure to LAN can modulate circadian rhythm genes involved in breast carcinogenesis process [13].
The endogenous and self-sustained circadian rhythm is generated and maintained in the suprachiasmatic nucleus (SCN) and it interacts with the peripheral clocks by sending signals to peripheral tissues [14]. Around 20 genes have been found to control circadian rhythm in the SCN and peripheral tissues [15]. The biological molecular clock is composed of several genes forming auto-regulatory transcriptional and translational feedback loops with both positive and negative regulators [15], [16]. These core clock genes include ARNTL1 or BMAL1 (aryl hydrocarbon receptor nuclear translocator-like or brain and muscle ARNT-like 1), CLOCK (circadian locomotor output cycles kaput, clock circadian regulator) [17], PER1, PER2, PER3 (period circadian clock) [18], CRY1, CRY2 (cryptochrome circadian clock) [19], TIMELESS (timeless circadian clock) [20], CSNK1A1 (casein kinase 1, alpha 1) [18], and NPAS2 (neuronal PAS domain protein 2) [21]. Positive clock regulators BMAL1, CLOCK, NPAS2 form a heterodimer-inducing transcription of negative clock regulators PERs and CRYs, while BMAL1/CLOCK or BMAL1/NPAS2 heterodimers bind to the E-box (CACGTG) regulatory element in the promoter region of PER and CRY genes [17]. The CSNK1A1 enzyme that phosphorylates PERs and CRYs are present in cytoplasm and are translocated into the nucleus where, in the form of a protein complex, they inhibit BMAL1 expression [22]. Interestingly, several clock transcription factors, like canonical BMAL1 and CLOCK [23], but also DBP, RORA, RORB, RORC, NR1D1, NR1D2 can modulate genome-wide rhythmic expression of clock-controlled genes due to recognition of specific sequences in promoter regions of those genes such as D-boxes, E-boxes, RORE elements, and cAMP response elements [24], [25], [26], [27], [28]. Indeed, circadian oscillation of expression can be observed in 7–21% of mammalian transcriptome in various peripheral tissues [24], [25], [29]. Therefore, it appears that circadian genes may be involved directly or indirectly in several critical molecular processes like cell cycle arrest, DNA damage repair, cell proliferation, maintenance of genomic stability, inflammation, oxidative stress and apoptosis, thus playing a pivotal role in carcinogenesis [20], [30], [31], [32].
Circadian disruption in knock-out mouse strains and in human studies has been recognized in a broad range of cancers, including breast, lung, colorectal, ovarian, pancreatic cancer, and hematologic malignancies in humans [32]. To add, alterations of CLOCK, PERs, CRYs and TIMELESS gene expression, often related to relevant gene methylation have been linked with breast cancer etiology and prognosis [33]. Interestingly, circadian genes deregulation, often accompanied by clock-controlled gene changes, were also observed in other health problems, such as premature death and aging, cancer, metabolic syndrome, cardiovascular dysfunction, immune dysregulation, reproductive abnormalities, mood disorders, and learning deficits [32], [34].
Since circadian genetic polymorphism is recognized as a strong candidate for increased disease risk due to its relationship with circadian disruption and altered gene expression, circadian gene variants have been intensively investigated in various epidemiological studies to identify relationships with disease susceptibility. The majority of epidemiological studies have indicated that polymorphisms in circadian genes are implicated in diurnal preference and seasonality, psycho-behavioral factors and mental disorders, obesity, metabolic syndrome, type 2 diabetes and also cancer [35], [36]. So far, only a few studies have investigated the association between shift work and circadian rhythm polymorphism in relation to breast cancer occurrence. It is thus timely to review current epidemiological studies on circadian gene variants and breast cancer risk to update knowledge about candidate breast cancer genes.
We have systematically searched two databases (PubMed and EBSCO) using keywords “breast cancer”, “polymorphism”, “circadian” and “clock’ for studies published until July 2016. The initial search identified twenty-one publications, with fifteen meeting our criteria, being published in the English language and with an epidemiological focus on breast cancer. Altogether, there are 15 published epidemiological studies making use of 12 populations with different ethnicities and 5 studies including shift work, 12 genetic association case–control studies, including one genome-wide association study (GWAS), two nested-case control studies which investigated clock polymorphisms and one follow-up study. Epidemiological studies were also screened to evaluate whether multiple-testing quality control for genotyping was addressed (Table 1). All epidemiological studies analyzed putative link between minor alleles of investigated clock polymorphism and breast cancer, testing dominant and/or additive models for minor alleles. Ten genetic association studies, including one GWAS study show that polymorphisms of circadian genes are significantly associated with breast cancer risk (Table 2). Moreover, four nested case–control and one case–control studies indicate significant impact of shift work on association between circadian genes polymorphism and breast cancer risk (Table 3).
Section snippets
Circadian genes polymorphism in breast cancer – results from genetic association studies
Epidemiological studies on circadian gene variants and breast cancer risk among different female populations have been conducted since 2005 (Table 1). Candidate breast cancer variants and single nucleotide polymorphisms (SNPs) were analyzed in positive BMAL1, CLOCK, NPAS2 and negative CRYs, PERs clock regulators and TIMELESS, indicating several statistically significant associations between clock SNPs and breast cancer susceptibility (Table 2). Unfortunately, the majority of these significant
Circadian genes polymorphism in breast cancer – shift work impact
Four of the five nested case–control and case–control studies indicate the impact of night work on association between circadian genes polymorphism and breast cancer risk, taking into account major and minor homozygotes and shift work intensity (Table 3). It should be underlined that night shift work duration was comparable in USA [78], Canadian [39] and French [42] study (<2 and ≥2 years of nigh shift work), while in German study it was <1 and ≥1 year of nigh shift work [37]. The most
Conclusion
In total, there have been fifteen epidemiological studies examining the possible link between clock gene variants (mainly SNPs) and breast cancer risk, including five studies focused on night shift workers. What underpins these studies is a view that the majority of breast cancer genetic association studies are relatively large, and have been conducted in Caucasian populations (e.g. five studies involving hospital-based Connecticut case–control population with over 91% participants with
Acknowledgments
This work was supported by the Norway grants in the framework of Polish-Norwegian Research Program carried out by the National Centre for Research and Development (Pol-Nor/196940/22/2013 – CLOCKSHIFT) and the National Science Center, Poland (2014/15/N/NZ5/01671).
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