The Role of Serotonin in Breast Cancer

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) is a hormone that functions as a neurotransmitter as well as a hormone. Recently, the link between 5-HT and metabolic diseases has been revealed. Breast cancer is one of the most common cancers in women throughout the world. Serotonin is a monoamine that is produced and secreted by breast epithelial cells. It is essential for maintaining epithelial homeostasis during pregnancy, lactation, and involution. The role of 5-HT in tumor cell biology in breast cancer is not completely understood. In this review, we focused on the impact of 5-HT on breast cancer.

Cancer is a disease caused by cell mutations and uncontrolled cell proliferation.[1-6] Angiogenesis, continuous proliferation, vascularization, metastasis, invasion, self-sufficiency in growth signals, insensitivity to growth inhibition, and unlimited replicative potential are the basic characteristics of cancer cells.[6-9] Breast cancer is one of the most common cancers in women and the main cause of cancer deaths worldwide.[10-15] Every year, 1.7 million new cases of breast cancer are detected. Despite recent advancements, its prevalence is growing.[6,16] Serotonin (5-hydroxytryptamine, 5-HT) is an amine that is produced from tryptophan, an important amino acid.[7]An important neurotransmitter 5-HT functions as a hormone outside of the central nervous system (CNS) and has many receptor subtypes.[10] Serotonin promotes the growth of tumor cells. It also regulates tumor growth by regulating cell proliferation, metastasis, invasion, and angiogenesis.[17,18]

BREAST CANCER

Cancer was detected in evidence of fossilized bone tumors (osteosarcoma) found in Ancient Egyptian mummy research circa 1600 BC. According to the oldest records in 1500 BC it is thought that breast cancer was the first disease to be detected at that time.[1,19] Hippocrates defined cancer between 480 and 370 BC.[20,21] It comes from the Greek word “karkinos (carcinoma)” and is used to describe malignant tumors.[1] The breast is mainly composed of adipose and fibroglandular tissues. In females, the mammary glands[22,23] responsible for lactation are found in the breasts. Mammary glands are composed of 12 to 20 lobes, each of which contains numerous smaller lobules. These smaller lobules have grape-like clusters of alveoli that contain mammary secretory epithelial cells, which produce milk during lactation. Breast cancer is divided into two categories based on the histological characteristics of the tissue.[1,24] Cancer that occurs in the breast lobes is known as lobular carcinoma in situ, while cancer that occurs in the canal structure is known as ductal carcinoma in situ. [24,25] Breast cancer is one of the most common cancers in women.[12,26,28,29] Cancer treatment options include surgery, radiation therapy, and chemotherapy.[10,30] Breast cancer susceptibility gene 1 (BRCA1)[31-33] and BRCA2[34-36] is the most important biological breast cancer genes.[6,14,15,24,37] Mutations in these genes cause cancer. The immune system plays an essential role in breast cancer. The immune-inhibitory receptor programmed death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1)[38-41] cause the tumor to escape the immune system.[38] Breast cancer is a disease that causes malignant tumors as a result of the excessive proliferation of epithelial cells lining the lobules and ducts. Breast tumors are the first epithelial tumors to take the form of cancer stem cells.[10] The mammary gland’s effectiveness also renders it defenseless against breast disorders such as mastitis and cancer. These disorders are caused by a malfunction in the main homeostatic regulatory system that regulates mammary gland development and function.[7] Since tumors have different characteristics, various molecular states are classed as a single disease in the diagnosis and treatment of breast cancer. Breast cancer stem cells are resistant to treatment. Therefore, breast cancer recurrence is considered. It is essential to target these cells in order to eliminate the symptoms of breast cancer.[10] Breast cancers are divided into various subtypes based on the expression of estrogen receptor (ER) and progesterone receptor (PR) and the presence of human epidermal growth factor receptor 2 (HER2)-negative cells.[10,11,13] Breast cancers are classified into three types: hormone-sensitive, HER2-positive, and triple-negative breast cancer (TNBC/ER negative, PR negative, and HER2 negative).[42] Triple-negative breast cancer is the most severe subtype, with a high risk of recurrence, aggressiveness, a poor prognosis, poor differentiation, and few treatment choices.[11,13,24,43]

SEROTONIN

Serotonin, like epinephrine, is a biogenic monoamine that has been remarkably conserved throughout evolution.[44.45]Serotonin is important in the many functional brain mechanisms that underlie aggression, appetite, mood swings, motor abilities, pain, and sleep.[46,47] In 1948, 5-HT was isolated and described by Rapport et al.[45] and Gaddum and Hameed [48] revealed the existence of 5-HT in the brain in 1954 and demonstrated that 5-HT had a function in the gut.[49] Serotonin was named after the Latin word serum and the Greek word tonic. [45] Tryptophan hydroxylase (TPH), a rapidly restrictive enzyme with two isoforms TPH1 and TPH2, converts tryptophan, a necessary amino acid, to 5-HTP in mammals.[45,47,50] The TPH1 is expressed mostly in the pineal gland, pancreatic beta-cells, and enterochromaffin cells of the intestine. The THP2 is expressed by neurons in the CNS. Enterochromaffin cells in the gut are the most abundant source of 5-HT in the body, accounting for 90-95% of 5-HT expression.[48,51,52] Serotonin has long been known to play an important function in platelet aggregation and vasoconstriction, but 5-HT has lately been shown to play other roles in metabolism.[47] Presynaptic neurons in the raphe nucleus generate and store 5-HT in vesicles in the adult brain. E14 produces a high level of 5-HT in some tissues as a supplement to the raphe nucleus; these tissues are enterochromaffin and myenteric cells in the pineal gland and intestine.[52-54]

Serotonin is a neurotransmitter and peripheral signaling molecule that influences hemostasis, immune function, gastrointestinal physiology, and other physiological systems. Many 5-HT receptors are found in endocrine, cardiovascular, immunological, and gastrointestinal tissues. Many diseases have been linked to serotonin, including gastrointestinal disorders, cardiac arrhythmia, hypertension, depression[55], anxiety, schizophrenia, obsessive-compulsive disorders, addiction, and Parkinson’s disease.[56,57] Serotonin regulates and functions the brain in many ways, including appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction, endocrine regulation, neuronal and glial cell development, and control of the synaptic connection.[58,59] It is essential for controlling all brain activities, and defects in the serotonergic system can lead to the development of a variety of mental and neurological disorders.[18,57,60] It has numerous important effects on serotonin vascular biology, vascular resistance, and blood pressure regulation, as well as hemostasis and platelet function.[60] The quantity of 5-HT in the blood ranges between 0.7 μM and 2.5 μM.[51] The fact that 5-HT is released by platelets is critical for the healing process in normal organ damage.[61] Serotonin acts on cells by activating a random one of 15 different receptors from seven different families (5-HT1 to 5-HT7), each with its own signal transduction mechanism and functional role.[44,56] The serotonin reuptake transporter (SERT) is another essential 5-HT receptor involved in the uptake and clearance of 5-HT into the cell.[7] It is encoded by the SLC6A4 (17q11.1-q12) gene in humans. It is a monoamine transporter protein that transports 5-HT into cells. It is also known as sodium-dependent 5-HT transporter.[51] Serotonin is a cancer-activating agent.[51,62] Inhibition of tumor development and angiogenesis is achieved by 5-HT’s stimulation of dopamine. There is insufficient data on the expression of 5-HT and dopamine receptors in cancer.[63] Serotonin’s autocrine/paracrine activity is a critical homeostatic variable in mammary gland development. Many of the effects of 5-HT in breast tissue are aided by the 5-HT7 receptor, which has been suggested to be significant.[7] Serotonin has recently emerged as a growth factor in malignancies such as carcinomas, gliomas, and carcinoids. There is evidence that 5-HT has a role in cancer cell invasion, metastatic expansion, and tumor angiogenesis. The signaling pathways by which serotonin promotes cancer progression are unclear, and only a fraction of some cancers are understood.[48,51,61] Anticancer effects of serotonin receptor antagonists have been observed in numerous malignancies, including bladder cancer, prostate cancer, breast cancer, colorectal cancer, carcinoid, and small-cell lung cancer.[48]

THE LINK BETWEEN BREAST CANCER AND SEROTONIN

Serotonin is a neurotransmitter, growth factor, and hormone that has a variety of physiological functions. It has recently been demonstrated to be a metabolic hormone that influences glucose homeostasis and obesity, with a link between circulating 5-HT levels and metabolic disturbances.[47] Breast cancer is the most frequent type of cancer in women worldwide, with few prognostic markers identified. During pregnancy, lactation, and involution, serotonin acts as a local regulator to modify epithelial homeostasis.[48,61] One of the local factors produced and secreted by breast epithelial cells is monoamine 5-HT as shown in Figure 1. It has been demonstrated that it acts as a 5-HT stimulator in the development of breast cancer.[43] The molecular goals of selective antagonists are expressed in 5-HT-producing breast tumors and breast cancer cell lines, indicating that 5-HT necessarily plays a functional role in these cells. [10] The bioactive level of 5-HT in the mammary gland is actively regulated by means of TPH, SERT, and monoamine oxidase.[7] Except for cancer cells, serotonin has been observed in many studies to have only a weak effect on cell growth. 5-HT’s 5-HT1 and 5-HT2 receptors act on cell growth.[61] Serotonin is known to be effective in tumor development, metastasis, and cancer types.[17,48,64]

Figure 1. Serotonin synthesis and enzymes in breast tissue.

Serotonin receptors are expressed in breast cancer tissues, and this expression is also related to estrogen and HER2 receptor expression.[65] Epithelial homeostatic balance has to do with the progression of breast cancer in the mammary gland. Serotonin 5-HT2A receptors trigger the tumor formation structure of breast cells.[17,48,61] The function of serotonin can change with environmental factors and drugs.[51] In breast cancer, 5-HT plays a crucial role in tumor development by stimulating the proliferation of breast cancer cells and activating the characteristics of the cellular environment in which it interacts to keep unsuitable cells alive.

Serotonin increases the rate of cell proliferation and provides the advantage of promoting the proliferation of breast cancer cells by providing an escape from apoptosis. Breast cancer cells produce a lot of 5-HT, and free 5-HT plasma levels are used as an early detection marker in breast cancer. The biology of serotonin in breast cancer cells is not yet fully known, and also the mechanisms by which 5-HT is thought to induce carcinogenesis have not yet been resolved too.[66] Serotonin levels are known to play a very important role in tumor growth.[48] Selective serotonin reuptake inhibitors (SSRIs)[67] are known to increase the likelihood of malignancy.[68] Serotonin increases the proliferation rate of cancerous cells and is known to provide proliferative benefits to breast cancer cells by providing an escape from apoptosis.[66] The effect of 5-HT, which acts as an oncogene, on tumor growth has not yet been resolved. This can be explained by the fact that tissue-specific expression of 5-HT receptors is carried out. The effect of serotonin on the stimulation of mitosis division is dose-dependent, while higher doses promote cell proliferation, and lower doses cause tumor vessels to shrinkage and inhibit tumor growth. There are many 5-HT receptor-directed drugs, such as SSRIs, which are used in the treatment of central nervous system patients, and are being evaluated for use as anticancer agents. Selective serotonin reuptake inhibitors increase the level of 5-HT in the synaptic gap and plasma but do not contribute to tumor formation.[48] The complex function of serotonin in the vessels is the result of its combination with many different receptors. The vasoconstrictive effects of the agonists of 5-HT and 5-HT in the blood vessels feeding the tumor tissue are under the control of the arterioles and thus are effective in reducing the development of malignants that are altered by controlling the tumor blood flow. Different receptors of serotonin are located in the blood vessels that feed tumors. The 5-HT1D and 5-HT2B receptors are very much expressed in all the inner surface cells of the vessels in the good and bad tumor tissues. Immunohistochemical analyses of samples obtained from breast cancer patients revealed the expression of 5-HT1A and 5-HT2B receptors in the blood vessels of malignant and non-malignant cancer cells.[18] The effect on the tumor vascular system is a mixed process and depends on its interaction with 5-HT receptors.[48] Serotonin, 5-HTR1B, and 5-HTR2B receptors stimulate tumor angiogenesis through interaction. Cancer cells are able to stimulate the proliferation of tumor cells through 5-HT receptors.[63] High levels of 5-HTR2B receptor are expressed in endothelial cells of breast, kidney, and pancreatic cancers.[66] Antagonists of serotonin receptors have been found to inhibit the proliferation of cancer cells, but the suitability of the use of the 5-HT receptor for pharmacotherapy is not certain.[18] The 5-HTR2B antagonists expressed in breast cancer are LY272025 and SB-206553 molecules.[70,71] Selective serotonin reuptake inhibitors slow tumor growth.In cancer cells, 5-HT is used to increase the expression of this molecule, which is an immune inhibitor expressed as PD-L1. This immunoinhibitory molecule binds to T cells, which are immune cells. Thus, they can escape from T cells that are programmed to destroy their cancerous cells. Studies have shown that SSRIs inhibit this mechanism. Such antidepressants cause immune cells to recognize and destroy cancer cells again.[69] Serotonin promotes the development of cancer by affecting cancer cells by enabling the proliferation of cancer cells through cell cycle progression, autophagy, and the suppression of apoptosis.[51]

It is known that 5-HT has a role in the mammary gland process.[48,61] Serotonin supports the development of cancer by affecting cancer cells by acting in the cell cycle, autophagy, and apoptosis processes.[51] Serotonin is one of the underlying causes of many diseases. The fact that serotonin underlies other metabolic diseases has also recently emerged. [47] One of these diseases is cancer.[43,62,51] Serotonin, which exists in the structure of the mammary gland, serves in breast cancer. It is, which plays a role in breast development, also effective in the development of cancerous tissue in breast cancer. It has functions such as the development of cancerous tissue, the formation of angiogenesis, and escape from apoptosis. Breast cancer is so much in its structure that it can produce a lot of 5-HT. This is used as an early diagnosis of breast cancer by looking at the free 5-HT levels in the plasma. It is clear that serotonin has a negative function in cancer, but this complex mechanism has not been fully solved.[66] A solution to prevent the negative effect of serotonin in cancer has not been definitively found. The biggest reason why the mechanism of serotonin in cancer cannot be solved is the tissue-specific expression of 5-HT. For example, the effect of high levels of 5-HT on cancer supports tumor cell proliferation, while low amounts of 5-HT prevent the development of tumor tissue by contracting the vascular structure in cancerous tissue.[48] Although antagonists of 5-HT inhibit the development of cancer, information on their use as a treatment is not conclusive.[18] The task of antagonists is to bind to a receptor and replace the compound that stimulates the receptor to which it binds, preventing the result that occurs when that receptor is stimulated. These are LY272025 and SB-206553, known antagonists of the highly expressed 5-HTR2B receptor in breast cancer.[70,71] However, these antagonists do not have studies in breast cancer. Studies on antagonists of 5-HT receptors in breast cancer are insufficient. Studies on 5-HT antagonists in cancer should be conducted. Deeper studies should be done on the antagonists of the 5-HT receptors that are specialized in breast cancer.

In conclusion, 5-HT is involved in cancer, but this mechanism has not been solved. Serotonin has a role in breast cancer, with highly expressed 5-HT being used as a marker for early detection. No solution has been found to prevent serotonin’s role in cancer. Since serotonin is such a deep issue as cancer, studies on the relationship between 5-HT and cancer are therefore scarce. Although serotonin antagonists have been shown to prevent the development of cancer, their use for treatment is not certain. More studies on serotonin antagonists should be done.

Cite this article as: Barmanbay BN, Altuntaş İ, Erbaş O. The Role of Serotonin in Breast Cancer. JEB Med Sci 2022;3(3):221-226.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The authors received no financial support for the research and/or authorship of this article.

The figure used in this review was created with BioRender (BioRender.com).

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