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 beginning to link disruptions in the circadian rhythm to a variety of disorders. Alzheimer’s, stress, migraines and cancer are some of the diseases that have been linked to a body clock being disrupted 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 high”. This, the researchers suggest, could explain why people who work night shifts are at an increased risk of cancer. The latest studies conducted at Texas A&M University suggest that the same Per2 gene may have a protective effect against the appearance of breast K. The function of Per2 is to regulate the circadian rhythms present within each cell.
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 in a structure known as the suprachiasmatic nucleus (SCN). The function of Per2 within the mechanism of our biological clock is wider than previously thought. In fact, not only do we have a central clock [the SCN], 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 light, light enters the 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 oscillate in 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 Texas A&M team led by prof. Porter has determined a further role for Per2 in addition to that of timing. Suppressing Per2 in mice led to abnormally developed mammary glands in rodents. They have a kind of bi-powerful phenotype; they’re actually halfway to cancer, already haviong 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. Additionally, most breast cancers have low Per2 expression, which suggests that the body clock gene may protect against breast cancer. Therefore, Per2 functions as a tumor suppressor gene associated with cellular identity. There are already studies showing a relationship between reduced Per2 levels and some types of breast cancer, which are more invasive. Hence, scientists believe that there is a direct relationship. Other independent groups have shown that during the transformation of breast cells from normal to cancer, the subversion of rhythms by the protein ZNF704 occurs.
It has been seen to act as a transcriptional repressor by interacting with the SIN3A complex for gene repression. Genome-wide analyzes of the transcriptional targets revealed that the ZNF704 / SIN3A complex represses a panel of genes, including Per2, that are critically involved in circadian clock function. 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 the growth and metastasis of breast cancer in vivo. Consistently, the expression level of ZNF704 was inversely related to that of Per2 in breast cancers and the high level of ZNF704 was related to advanced histological grades, lymph node positivity and poorer prognosis. These findings lead researchers to think that ZNF704 is an important circadian clock regulator and a potential driver for breast cancer. Independent analyzes by other research groups have shown that variations in Per2 and the other parallel regulator, BMAL1, are evident in all four stages of the tumorigenesis process: from the promotion stage (stage 1) to that of 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 a breast tumor. In addition to the above, researchers have already made connections and hypotheses about the role of female night work and the risk of developing breast cancer for almost a decade. The largest investigations were done on cohorts of nurses on night shifts in healthcare settings. The “night light” factor has been relied more on that of the interruption of normal night sleep patterns. In fact, light is a suppressor of the brain production of melatonin, a hormone that regulates sleep, some female functions and the daily hormonal rhythms. Not coincidentally, melatonin is also a suppressor of the proliferation of several lines of cancer cells, including those of breast cancer. Melatonin plays a regulatory role in the HPG axis by suppressing the synthesis of ovarian estrogens. Melatonin is also a powerful 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 diminishes when tumors take hold by growth and metastasis in an organism with weakened immune defenses. 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 coincidentally, it is common opinion that a good restful sleep keeps the immune defenses efficient, a view widely confirmed by the scientific literature. Obviously in complete darkness, because laboratory investigations have shown that exposure to artificial night light (intensity between 2500-3000 lux) lowers the anti-oncogenic power of melatonin. The data was confirmed by analyses of two large cohorts of nurses, NHS I and II studies. But as early as twenty years ago, a retrospective case-control analysis revealed that the risk of breast cancer is increased in women who often reported not sleeping 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.
Yang C et al. Cancer Res 2020; 80(19):4114-4128.
Lin HH et al. Integr Cancer Ther. 2019; 18:1534735419836494.
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):2876-84.