Of sight, and insight into melatonin’s role in breast cancer?

A Deucalione, melatonin, is synthesized by the pine cone-shaped gland of the cerebrum, named as the conarium or epiphysis cerebri. Since the 17th-century philosopher René Descartes hypothesized the brain’s pineal gland in order to represent the location of the homo sapiens soul, paleontologists described it as an ancestral “third eye,” and modern psychology declares perception beyond physical visual function, which remains poorly understood to date¹. The pineal gland is not only a crucial organ for melatonin but also vital for many activities; for example, we postulated that pinealectomy leads to many morphological alterations, including interstitial cell morphology, of rat ovaries that are associated with functional changes in steroidogenesis and attenuation in progesterone receptor expression².

This hormone is involved in the regulation of sleep, circadian rhythms, breast milk, and gut-brain signaling. In addition to its role in sleep-wake cycles, melatonin possesses antioxidant, anti-inflammatory, and antitumor properties³. Breast cancer is the most common cancer among women worldwide, accounting for over 2 million new cases each year. The development of breast cancer is a complex process that involves multiple genetic and environmental factors⁴,⁵. Hormones, such as estrogen and progesterone, are known to play a crucial role in the development of this malignity⁶. Melatonin has been revealed to inhibit the growth of breast cancer cells both in vitro and in vivo. A posteriori, melatonin has been found to attenuate the proliferation of breast cancer cells and induce apoptosis, or programmed cell death, in cancer cells. Of note, this effect is thought to be due to melatonin’s ability to reduce oxidative stress and inflammation, two factors that are known to contribute to the development of cancer. Melatonin, per se, is a hormone with different oncostatin actions, which are particularly effective in breast carcinoma⁷,⁸. It displays antioxidant properties via the scavenging of free radicals, protecting cells from carcinogen-mediated deoxyribonucleic acid modifications of oxidative damage, which leads to preventing the initiation of malignant transformation⁹,¹⁰. Of note, melatonin is also reported to exhibit antiproliferative effects on Michigan Cancer Foundation-7 (MCF-7) human breast cancer cells by inducing a delay in the cell cycle G1-S transition. As such, a subsequent accumulation of the cells in the G0/G1 phase¹⁰ emerges, which gives rise to arresting the cell cycle in the G1 phase and attenuating the invasion and migration of breast cancer cells. Moreover, this hormone possesses oncostatic activity using antiangiogenic actions in breast cancer cells¹⁰-¹³. In addition, Veiga and colleagues¹⁴ reported a systematic review and meta-analysis, including a sum of 570 articles, and 9 manuscripts in which the authors analyzed women with breast cancer and control cases, of which 10 and 90% were in the reproductive period and after menopause, respectively. They emphasized that the lowest level of melatonin had been found in approximately 55% of studies with breast cancer in post-menopause and postulated that low levels of melatonin might be a risk factor for this malignity.

Recently, melatonin’s role in the tumor microenvironment has been notified. To this end, laying out the paracrine interactions between malignant epithelial and proximal endothelial cells via downregulation of vascular endothelial growth factor expression in human breast cancer cells, which leads to significant attenuation in angiogenesis, has been emphasized¹⁵. Besides its direct effects, melatonin modulates the activity of estrogen receptors, which play a key role in breast cancer development. In addition, melatonin attenuates the expression of estrogen receptors in breast cancer cells, which may reduce the availability of estrogen for these cells in order to utilize in promoting their growth. The antitumor properties of melatonin have also been observed in animal models of breast cancer, such as inhibiting the growth of breast tumors and reducing the incidence of mammo-malignity, which are due to melatonin’s ability to enhance the immune system response to cancer cells¹⁶. Despite the promising results of these studies, the clinical implications of melatonin in the prevention and treatment of breast carcinoma are not yet clear. While melatonin is safe and well tolerated in humans, more research is required to determine the optimal dose and timing of melatonin supplementation for breast cancer prevention and treatment modalities. Principally, although diagnosis¹⁷,¹⁸ remains crucial for malignant phenomena, the debate is still ongoing on diagnostic tools as well as therapeutic agents in order to pay dividends for providers. In conclusion, melatonin appears to play a significant role in the regulation of breast cancer growth. Its ability to inhibit the proliferation of breast cancer cells, modulate estrogen receptor activity, and enhance immune system function makes it a promising candidate for preventing and managing breast cancer. As a matter of fact, this issue merits further investigation.

REFERENCES

• ^1.
  Lane R. Of sight, and insight. The Lancet. 2023:401(10371):97. https://doi.org/10.1016/S0140-6736(22)02589-2
  » https://doi.org/10.1016/S0140-6736(22)02589-2
• ^2.
  Soares JM, Simões MJ, Oshima CT, Mora OA, Lima GR, Baracat EC. Pinealectomy changes rat ovarian interstitial cell morphology and decreases progesterone receptor expression. Gynecol Endocrinol. 2003;17(2):115-23. PMID: 12737672
• ^3.
  Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin--a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 2011;93(3):350-84. https://doi.org/10.1016/j.pneurobio.2010.12.004
  » https://doi.org/10.1016/j.pneurobio.2010.12.004
• ^4.
  Kesicioglu T, Sengul I, Aydın I, Vural S, Sengul D. Revisiting surgical management of breast cancer in a geriatric population. Rev Assoc Med Bras (1992). 2022;68(11):1504-8. https://doi.org/10.1590/1806-9282.20220961
  » https://doi.org/10.1590/1806-9282.20220961
• ^5.
  Prokop J, Maršálek P, Sengul I, Pelikán A, Janoutová J, Horyl P, et al. Evaluation of breast stiffness pathology based on breast compression during mammography: Proposal for novel breast stiffness scale classification. Clinics (Sao Paulo). 2022;77:100100. https://doi.org/10.1016/j.clinsp.2022.100100
  » https://doi.org/10.1016/j.clinsp.2022.100100
• ^6.
  Hilton HN, Clarke CL, Graham JD. Estrogen and progesterone signalling in the normal breast and its implications for cancer development. Mol Cell Endocrinol. 2018;466:2-14. https://doi.org/10.1016/j.mce.2017.08.011
  » https://doi.org/10.1016/j.mce.2017.08.011
• ^7.
  Gutic B, Bozanovic T, Mandic A, Dugalic S, Todorovic J, Stanisavljevic D, et al. Programmed cell death-1 and its ligands: current knowledge and possibilities in immunotherapy. Clinics (Sao Paulo). 2023;78:100177. https://doi.org/10.1016/j.clinsp.2023.100177
  » https://doi.org/10.1016/j.clinsp.2023.100177
• ^8.
  Laborda-Illanes A, Sánchez-Alcoholado L, Castellano-Castillo D, Boutriq S, Plaza-Andrades I, Aranega-Martín L, et al. Development of in vitro and in vivo tools to evaluate the antiangiogenic potential of melatonin to neutralize the angiogenic effects of VEGF and breast cancer cells: CAM assay and 3D endothelial cell spheroids. Biomed Pharmacother. 2023;157:114041. https://doi.org/10.1016/j.biopha.2022.114041
  » https://doi.org/10.1016/j.biopha.2022.114041
• ^9.
  Blask DE, Sauer LA, Dauchy RT. Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2002;2(2):113-32. https://doi.org/10.2174/1568026023394407
  » https://doi.org/10.2174/1568026023394407
• ^10.
  Bhattacharya S, Patel KK, Dehari D, Agrawal AK, Singh S. Melatonin and its ubiquitous anticancer effects. Mol Cell Biochem. 2019;462(1-2):133-55. https://doi.org/10.1007/s11010-019-03617-5
  » https://doi.org/10.1007/s11010-019-03617-5
• ^11.
  Cos S, Mediavilla MD, Fernández R, González-Lamuño D, Sánchez-Barceló EJ. Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro?. J Pineal Res. 2002;32(2):90-6. https://doi.org/10.1034/j.1600-079x.2002.1821.x
  » https://doi.org/10.1034/j.1600-079x.2002.1821.x
• ^12.
  González-González A, González A, Alonso-González C, Menéndez-Menéndez J, Martínez-Campa C, Cos S. Complementary actions of melatonin on angiogenic factors, the angiopoietin/Tie2 axis and VEGF, in co-cultures of human endothelial and breast cancer cells. Oncol Rep. 2018;39(1):433-41. https://doi.org/10.3892/or.2017.6070
  » https://doi.org/10.3892/or.2017.6070
• ^13.
  González A, Alonso-González C, González-González A, Menéndez-Menéndez J, Cos S, Martínez-Campa C. Melatonin as an Adjuvant to Antiangiogenic Cancer Treatments. Cancers (Basel). 2021;13(13):3263. https://doi.org/10.3390/cancers13133263
  » https://doi.org/10.3390/cancers13133263
• ^14.
  Veiga ECA, Simões R, Valenti VE, Cipolla-Neto J, Abreu LC, Barros EPM, et al. Repercussions of melatonin on the risk of breast cancer: a systematic review and meta-analysis. Rev Assoc Med Bras (1992). 2019;65(5):699-705. https://doi.org/10.1590/1806-9282.65.5.699
  » https://doi.org/10.1590/1806-9282.65.5.699
• ^15.
  Alvarez-García V, González A, Alonso-González C, Martínez-Campa C, Cos S. Antiangiogenic effects of melatonin in endothelial cell cultures. Microvasc Res. 2013;87:25-33. https://doi.org/10.1016/j.mvr.2013.02.008
  » https://doi.org/10.1016/j.mvr.2013.02.008
• ^16.
  Menéndez-Menéndez J, Martínez-Campa C. Melatonin: an anti-tumor agent in hormone-dependent cancers. Int J Endocrinol. 2018;2018:3271948. https://doi.org/10.1155/2018/3271948
  » https://doi.org/10.1155/2018/3271948
• ^17.
  Sengul I, Sengul D. Hermeneutics for evaluation of the diagnostic value of ultrasound elastography in TIRADS 4 categories of thyroid nodules. Am J Med Case Rep. 2021;9(11):538-9. https://doi.org/10.12691/ajmcr-9-11-5
  » https://doi.org/10.12691/ajmcr-9-11-5
• ^18.
  Sengul D, Sengul I. Reassessing combining real-time elastography with fine-needle aspiration biopsy to identify malignant thyroid nodules. Am J Med Case Rep. 2021;9(11):552-3. https://doi.org/10.12691/ajmcr-9-11-9
  » https://doi.org/10.12691/ajmcr-9-11-9

• Funding: none.

Publication Dates

• Publication in this collection
  17 July 2023
• Date of issue
  2023

History

• Received
  03 Mar 2023
• Accepted
  30 Mar 2023