**6. Clinical trials and possible applications of melatonin in breast cancer treatment**

Clinical trials suggest that melatonin, due to its antioxidant, immunomodulatory, antiestrogenic, proapoptotic, and antiproliferative properties [82], can have a protective effect when administered along with other treatments such as chemotherapy or radiotherapy in patients suffering from advanced solid tumors [83]. The most outstanding results have been particularly obtained in breast cancer. Melatonin is an antitumor agent that enhances the beneficial effects of chemotherapy and radiotherapy and, on the other hand, it protects against the side effects of these therapies [83].

Melatonin has been shown to have anticancer actions in both *in vivo* and *in vitro* models and has been shown to reduce estrogenic hormones responsible for the normal and pathological growth of the mammary gland. It interferes with the activation of the estrogen receptor and counteracts the effects of estrogen at the tumor cell level, behaving as a SERM. Currently, 22 clinical trials examining the therapeutic value of melatonin in breast cancer are listed on the ClinicalTrials.gov. database. 5 of them are focused on the relief of symptoms associated with the tumoral process. The remaining 17 studies examine the therapeutic effects of melatonin either alone (9 trials) or as an adjuvant therapy associated with metformin, vitamin D, fluorouracil, doxorubicin, or toremifene (6 trials) or as an adjuvant therapy associated with radiotherapy (2 trials) in women already diagnosed with breast cancer.

*In vitro*, it has been demonstrated that melatonin increases the sensitivity of breast cancer cells to the effects of tamoxifen and anti-aromatase treatments [84, 85]. Furthermore, melatonin can behave as a preventive agent for breast cancer. Hormone replacement therapy (HRT) and cancer are controversial. Some clinical trials demonstrate that breast cancer is related to women who receive HRT, while others demonstrate that it does not affect increasing breast cancer risk [86]. Melatonin administration to patients who received previously HRT reduces the possibility of breast cancer development [87]. On the other hand, melatonin is able to reduce the breast cancer risk associated with obesity because this hormone prevents obesity and reduces aromatase expression and activity, thereby reducing the estrogen levels in adipose tissue [88]. Breast cancer risk is also associated with the exposure to some environmental pollutants with estrogenic properties (xenoestrogens). In particular, melatonin has been studied to counteract the estrogenic effects induced by cadmium [41, 89, 90], being useful to women who work in environments with these chemical pollutants. Besides, melatonin supplement has been shown to prevent chronodisruption induced by the exposure to light at night in women who work at night [91, 92].

Finally, melatonin has been shown to behave as an adjuvant agent that prevents the side effects of breast cancer treatments. In particular, melatonin has been studied for the improvement of sleep and life quality [93]. A prospective phase II trial showed that melatonin improves quality of sleep and life, social functions, reduces fatigue, and increases clock genes expression [93]. Another randomized, placebo-controlled, and double-blind clinical trial in postmenopausal breast cancer survivors showed that melatonin improved the quality of sleep but had no effect on hot flashes [94]. Melatonin as an adjuvant of anti-aromatase therapies prevents the osteoporosis induced by these treatments since this hormone promotes osteoblasts proliferation [95].

Besides, melatonin has been studied as the treatment of depressive symptoms and anxiety [96]. In particular, a study on women undergoing breast cancer surgery showed that melatonin reduced the risk of depressive symptoms [96]. Patients treated not only with tamoxifen but also con melatonin, felt an improvement in anxiety, asthenia, and symptoms of depression in comparison with those treated with tamoxifen alone [97].

In addition, melatonin is described as the prevention of breast radiation dermatitis [98]. Topical applications of melatonin emulsions to the management of skin toxicity during radiotherapy have been proposed [99]. In this sense, A phase II, prospective, double-blind randomized trial was designed to evaluate the efficacy of melatonin-containing cream (twice daily) in breast cancer patients during radiation treatment. In conclusion, patients in the melatonin group experimented a significantly reduced radiation dermatitis compared to those women receiving placebo [98].

On the other hand, melatonin is able to decrease the toxicity and increase the efficacy of chemotherapy [100]. It has been demonstrated that melatonin may protect patients against side effects such as stomatitis, asthenia, cardiotoxicity, and neurotoxicity caused by chemotherapy [101]. Melatonin reduces the hepatotoxicity induced by anti-aromatase therapies, such as letrozole [33]. Besides, melatonin decreases damage caused for chemotherapy drugs in blood cells [102]. In breast, lung, and gastrointestinal cancer patients, melatonin preserved against thrombocytopenia, stomatitis, asthenia, and neuropathy [103]. A hybrid compound of melatonin and tamoxifen has been patented (US8785501) to combine antiestrogenic properties of these compounds and reduce the side effects of tamoxifen, reducing the hyperproliferation uterine risk [104, 105]. Previous studies have also demonstrated that the percentage of 1-year survival in patients with advanced non-small-cell lung cancer treated with cisplatin and melatonin and in breast cancer treated with tamoxifen and melatonin increased in comparison with patients treated only with chemotherapy [97].

Despite the promising experimental results about the radioprotective role of melatonin, few clinical trials to verify the therapeutic usefulness of melatonin in humans have been conducted. In this sense, a preliminary study suggests that adjuvant melatonin plus radiotherapy may prolong the 1-year survival rate and improve the quality of life of patients affected by untreatable glioblastoma [106].

Thus, it exists a plethora of applications of melatonin, which could be a promising future target of study in the pathology of breast cancer.

### **7. Conclusions**

Breast cancer is a multifactorial disease. However, an explanation for the mechanism, which triggers this pathology remains unclear, and there lacks a hypothesis that can link all the mechanisms together. Over the years, researchers have studied the enormous range of biological activities of melatonin and its potential applications, including its effects as anticancer molecule. Recently, this indolamine has been described as a promising adjuvant in ER breast cancer prevention and treatment because of its antiestrogenic properties.

Herein we have proposed that a link between gut microbiota and melatonin levels exists, as well as between dysbiosis and circadian disruption, leading to an increase in the circulation of estrogen levels that is able to induce the development of breast cancer. On the other hand, butyrate is an SCFA synthesized by the intestinal

#### *DOI: http://dx.doi.org/10.5772/intechopen.106068 A Promising Challenge in the Link between Melatonin and Breast Cancer…*

microbiota that stimulates the melatonergic pathway by promoting the production of melatonin. Nevertheless, proinflammatory cytokines, stress, and diet factors stimulate the kynurenine pathway, moving Trp away from melatonergic pathway. This situation contributes to reducing melatonin levels and favoring NAS levels, increasing the NAS/melatonin ratio in breast cancer patients. It is important to highlight that NAS is implicated in survival, proliferation, and metastasis of breast cancer cells. In addition, this generates changes in gut microbiome and intestinal permeability caused by butyrate reduction and LPS levels increasing, inducing the inflammatory response, and decreasing melatonin production. All the foregoing contribute to breast cancer development.

Regarding changes in estrobolome composition as well as chronodisruption, favor the presence of deconjugated state of estrogens, which are the active form that increases breast cancer risk. We described the opposite action that melatonin exerts, unlike gut microbiome-derived β-glucuronidase activity. Melatonin is able to reduce the expression and activity of enzymes important in the biosynthesis of estrogens, reducing the estrogens levels and preventing breast cancer appearance.

On the other hand, melatonin regulates the desmoplastic reaction inducing the differentiation of preadipocytes into mature adipocytes, which do not express aromatase, lowering levels of estrogens and then reducing breast cancer risk. Melatonin achieves this differentiation through the stimulation of adipogenic cytokines (PPARγ and C/EBPα) and the inhibition of antiadipogenic cytokines (TNFα, IL-6, IL-11).

Although many in vitro and in vivo studies have been described, more clinical trials will be needed to describe the sensitizing properties of melatonin to the different treatments used to treat breast cancer, as well as to avoid their side effects. In addition, it will be important to explore the relationship between melatonin and the intestinal microbiota, since measuring the levels of this hormone together with the determination of the composition of the estrobolome of patients with breast cancer could constitute a promising tool for the development of biomarkers that help predict the development of breast cancer earlier. In conclusion, it will be crucial to maintain adequate levels of melatonin and a balanced composition of the microbiota to avoid developing breast cancer.
