A group of genes that code for different proteins found in many of our tissues and organs, our biological clocks regulate our circadian rhythms. These are behavioral and physiological changes that occur in response to the day and night cycle. More and more studies are starting to link circadian rhythm disruptions to a variety of disorders. Alzheimer’s, stress, migraines and cancer are some of the diseases that have been linked to a disrupted body clock by faulty genes that regulate it. The link between cancer and circadian rhythms has increasingly become the focus of medical research. A recent study, for example, revealed that two genes, called Bmal1 and Per2, produce a cancer-promoting protein when they “get the beats off.” This, the researchers suggest, could explain why people who work night shifts are at higher risk of cancer.
The latest studies conducted at Texas A&M University suggest that the Per2 gene itself may have a protective effect against the onset of breast cancer. Circadian rhythms are controlled by a “master clock” located in the brain. Specifically, the brain’s hypothalamus houses this central clock, which consists of more than 20,000 neurons grouped together in a structure known as the suprachiasmatic nucleus (SCN). The function of Per2 is to regulate the circadian rhythms present within each cell. But its function within the mechanism of our biological clock is wider than previously thought. Indeed, not only do we have a central clock, but each of our cells has one of these peripheral clocks and they are in coordination with the central clock. When you wake up in the morning and see the light, the light enters your brain and triggers this molecular mechanism that regulates the process (circadian rhythm).
Per2 — which is short for Period 2 — is responsible for encoding the “negative feedback” in this daily cycle, the researchers explain. The negative and positive feedback mechanisms are constantly in balance, going up and down. It gets up during the day, the other at night – they fluctuate over the 24 hours – but when you see the light, it resets it in the morning. When Per2 returns, it suppresses another gene called BMAL or CLOCK.” Using a transplant mouse model, the team led by Prof. Porter determined an additional role of the Per2 beyond that of timing. Suppressing Per2 in mice led to abnormally developed mammary glands in rodents. They have something of a bipotent phenotype; I’m actually halfway to cancer. They already have many of the characteristics that are seen in a pre-malignant cell. The gene, therefore, plays a key role in the differentiation and development of mammary gland cells.
Furthermore, most breast cancers have low expression of Per2, which suggests that the body clock gene may protect against breast cancer. Thus, ilPer2 functions as a tumor suppressor gene associated with cell identity. There are already studies showing a relationship between reduced levels of Per2 and some types of breast cancer, which are more invasive. Thus, scientists believe that there is a direct relationship. Other independent groups have proved that during the transformation of breast cells from normal to cancerous, the subversion of the rhythms by the protein ZNF704 occurs. This acts as a transcriptional repressor by interacting with the Sin3A complex for gene repression. Genome-wide analyzes of its targets revealed that the ZNF704-Sin3A complex represses a panel of genes, which includes Per2.
Overexpression of ZNF704 prolongs the period and attenuates the amplitude of the circadian clock. ZNF704 promoted the proliferation and invasion of breast cancer cells in vitro and accelerated breast cancer growth and metastasis live. Consistently, the expression level of ZNF704 was inversely correlated with that of Per2 in breast carcinomas, and high level of ZNF704 correlated with advanced histological grades, positive lymph nodes, and poorer prognosis. These results make the researchers think that ZNF704 is an important regulator of the circadian clock and a potential driver for breast carcinogenesis. Independent analyzes by other research groups have shown that variations in Per2 and BMAL1 are evident in all four stages of the tumourigenesis process: from promotion (stage 1) to complete anaplasia (stage 4).
This means that it takes time before the alteration of the “clock” proteins causes cellular alterations such as to lead to the appearance of breast cancer. This was posthumously demonstrated through the analysis of breast cancer cell lines that are usually studied in the laboratory. Various breast cancer cell lines (e.g. MCF-7, MDA-MB-231, SKBR3 and others) are frequently used to study the disease. Although these cell models are generally classified into several subtypes of breast cancer, each represents only a single stage of a progressive disease. For example, in research using three 21T-series cell lines, H16N2, 21PT, and 21MT-1, which represent disease progression from benign to metastatic, the researchers saw that circadian-dependent gene expression worsens with the higher stage. benign to malignant.
In addition to the above, in fact, it has been more than a decade since researchers have now made connections and hypotheses on the role of female night work and the risk of developing breast cancer. The largest surveys were done on cohorts of nurses working night shifts in health care settings. The “night light” factor was invoked more over that of the interruption of normal nocturnal sleep patterns. In fact, light is a suppressor of the cerebral production of melatonin, which regulates sleep, some female functions and daily hormonal rhythms. Not coincidentally, melatonin is also a suppressor of the proliferation of various tumor cell lines, including those of breast cancer. Melatonin plays a regulatory role in the HPG axis, suppressing ovarian estrogen synthesis; likewise melatonin is also a regulator of immune vigilance.
Melatonin is a repressor of the transcriptional activity of the estradiol receptor (ERα), which induces the proliferation of those breast cancers that are positive in its presence (ER+). Melatonin is also a powerful regulator of immune surveillance, which decreases when tumors take hold with the appearance of metastases when the immune defenses are weakened. Repeated disruptions to sleep and circadian systems can affect both innate and acquired immune function. Several studies have shown that a single night of sleep deprivation is associated with a reduced number of circulating natural killer (NK) lymphocytes, which are “born” anti-cancer guardians. Once again not by chance, it is commonly believed that a good night’s sleep keeps the immune system efficient, an opinion widely confirmed by scientific literature.
Obviously in complete darkness, because laboratory investigations have proved that exposure to artificial night light (intensities between 2500-3000 lux) lowers the anti-oncogenic power of melatonin. The data were confirmed by analyzes of two large cohorts of nurses, NHS Studies I and II. But as early as 20 years ago, a retrospective case-control analysis revealed that breast cancer risk increased in women who reported frequent sleeplessness at night when melatonin levels peak (around 1: 00), in the 10 years preceding the diagnosis. Further proof of how the sleep friend protects our health from all sides.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
MedComm 2020. 2022; 3(4):e189.
J Exp Clin Cancer Res. 2022; 41(1):67.
Biomedicine Rep. 2021; 15(6):98.
Lin HH et al. Clock Sleep. 2021 Nov 12; 3(4):598-608.
Yang C et al. Cancer Nothing 2020; 80(19):4114-4128.
McQueen CM et al. Development. 2018 Mar; 145(6).
Mocellin S et al. BMC Med. 2018 Feb 19; 16(1):20.
Samulin Erdem J et al. J Cancer 2017; 8(15):2