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Melatonin And Estrogen Positive Breast Cancer

Melatonin As A Biomarker Of Breast Cancer

Optimizing Treatment Options for HER2 / ER Breast Cancer using Models of Endocrine Resistance


Several retrospective studies have demonstrated significantly reduced melatonin levels in patients with breast cancer . However, no such association was observed in a large prospective study . Also, low plasma melatonin levels were not associated with breast cancer risk in high-risk individuals , perhaps due to melatonins antioxidant properties. Circulating melatonin levels were actually increased almost two-fold in smokers relative to controls , perhaps as a mechanism of detoxification.


Differences in melatonin production, particularly the magnitude of the nocturnal peak in the serum or the accumulation in breast cyst fluids in cancer patients may differentiate between different aspects of the disease, thus affecting treatment or ultimate outcome. Low levels of melatonin are associated with poor prognosis in breast cancer, based on measures of tumour aggression , differentiation and progression . Such parameters are potentially useful in staging a tumour and selecting a course of treatment, as they can provide information without the need for tumour biopsy.

Application Of Melatonin In The Clinical Trials For Breast Cancer Treatment

Melatonin has potential anti-cancer properties. But the results of clinical trials in human breast cancer therapy are insufficient, and it is not included in the treatment regimen . However, some reports are available in the field of the clinical trial of melatonin. The studies indicated that the cancer patients taking 20 mg of melatonin gave better clinical outcomes. The beneficial effects were remission of tumor volume and decreased rate of mortality . It was observed that sleep problem is a great challenge in breast cancer survivors, even after the completion of anti-cancer therapy. Li et al. reported that the first cycle of breast cancer chemotherapy disrupted the sleep-wake cycle, sleep quality, cognitive functions, and melatonin secretion. These are appeared as the side effects of breast cancer treatment. Application of 20 mg melatonin as an adjuvant prior to first cycle chemotherapy of breast cancer in a randomized, double-blinded, placebo-controlled trial with 36 participants showed improvement of cognitive performance, immediate and delayed episodic memory, sleep quality, and depressive symptoms . Previously, a randomized, double-blind, and placebo-controlled trial of melatonin had also been conducted on the patients undergoing breast cancer surgery. The application of 6 mg oral melatonin for 3 months significantly reduced the risk of depressive symptoms .

Estradiol Progesterone And Melatonin Serum Levels

Serum estradiol and progesterone levels were not significantly modified in the EPT and MEPT groups for the 3-month-old females in estrus . The lack of detectable differences in their levels is also consistent with the administered doses not altering estrous cycling in the young Neu mice, including cycle length, the number of cycles, and number of days in estrus over a 30 day period . However, there may be changes in their levels that were not measured, such as effects at other ages, at other times of the day/night, and at other stages or phases of the estrous cycle that may be relevant to the hormonal responsiveness in the mammary gland or other tissues/systems. For example, the increased uterine weights during the luteal phase in EPT, but not CON, mice result from modified estrogen and/or progesterone levels from the HT treatment. Therefore, the induced hormonal changes by EPT likely influence, not only the uterus, but also the mammary gland and other tissues.

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Melatonin As A Cancer Therapeutic Agent

Based on its potential oncostatic effects, melatonin has also long been considered as a possible cancer chemotherapeutic agent, most often in combination with established genotoxic or immunological regimens. Human data come mainly from a large series of studies by Lissoni and colleagues that used melatonin on relatively small numbers of patients, with many different types of cancer. Based on these studies , there are several grounds for invoking melatonin in cancer treatment, but most have been poorly investigated. For example, melatonin supplementation seems to promote general well-being in cancer patients , which might allow them to tolerate higher doses of toxic compounds or be more likely to complete standardised regimens of such compounds. Also, melatonin seems to be effective at preventing or reducing treatment-associated hypotension , thrombocytopaenia and cachexia however, it is not clear whether the greater tolerance for treatment elicited by melatonin administration has been exploited for greater overall treatment in any study.

Characteristics Of Case Patients And Control Subjects


Breast cancer diagnosis followed urine collection by a mean of 12.6 years among premenopausal case patients and 12.4 years among postmenopausal case patients .

The characteristics of case patients with breast cancer and control subjects are shown in Table . Premenopausal and postmenopausal case patients and control subjects were similar with respect to age, age at menarche, weight, height, body mass index, age at first birth, and the time for which urine samples were stored between collection and analysis.

Premenopausal case patients and control subjects were also similar with respect to parity, past use of hormones other than oral contraceptives, and menstrual cycle length. Among premenopausal women, a statistically significantly lower proportion of case patients than control subjects was using medication thought to suppress melatonin production , and a statistically significantly higher proportion of case patients than control subjects had a first-degree family history of breast cancer . A greater proportion of premenopausal case patients than of control subjects had previously used oral contraceptives , although this difference was not statistically significantly .

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Estrogen And Androgen Receptors Are Regulated By Melatonin

Additionally, to inhibition of androgen and estrogen production, melatonin can also control the intracellular levels and activity of the estrogen and androgen receptors. Therefore, the inhibitory action of melatonin on hormone-dependent cancer cells is primarily based on its ability to regulate estrogen and androgen signaling pathways again, most of the research has been conducted in breast cancer models. The pineal hormone decreases the levels of ER in MCF-7 cells and destabilizes the estradiol-ER complex preventing its binding to estradiol-responsive promoters , likely through interaction with calmodulin bound to ER . In prostate cancer cells, a melatonin-mediated nuclear exclusion of the androgen receptor has been described, indicating that melatonin might regulate the androgen receptor activity . In ovarian cancer, the effect of the pineal hormone on the ER levels remains unexplored, although it is known that melatonin decreases estradiol, increases progesterone, and downregulates androgen receptor, ER, and ER levels in oviducts and uteri of rats .

Melatonin Protection Against Invasion And Metastasis

A pilot phase II study including patients with metastatic breast cancer concluded that the administration of melatonin might induce tumor regression . Melatonin, at physiological concentrations , reduced the invasiveness of hormone-dependent MCF-7 cells and increased the levels of E-cadherin and beta1 integrin . Melatonin stimulated the Rho-associated protein kinase in MCF-7 cells and in an in vivo model of breast cancer metastasis in the lung . The pineal hormone activated glycogen synthase kinase 3 by inhibiting Akt phosphorylation, inducing -catenin degradation, and thus inhibiting epithelial-to-mesenchymal transition . After treatment with 1mM melatonin, MCF-7 cells reduced cell migration and invasion E-cadherin expression was increased, whereas OCT4, N-cadherin, and vimentin were reduced . In MCF-7 cells overexpressing Her2, melatonin repressed the epithelial-to-mesenchymal transition by suppressing RSK2 expression . In ovarian cancer cells, ZEB1, ZEB2, vimentin, and snail, genes related to epithelial-to-mesenchymal transition, were downregulated after melatonin treatment .

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Serum Collection For Hormone Assays

Whole blood was obtained via cardiac puncture at necropsy from 3-month-old female mice in estrus and transferred to ice-cold Serum Gel S/1.1 tubes . After clot retraction, tubes were centrifugation at 16,500 g for 5 min and stored at 20°C. Serum levels of estradiol were assessed using the Double Antibody Estradiol kit and levels of progesterone were assessed with the Coat-A-Count® Progesterone kit according to manufacturer’s protocol.

Melatonin Boost A Key To Fighting Breast Cancer

Adjuvant Hormonal Therapy for Estrogen Receptor Positive Early Stage Breast Cancer – Mayo Clinic
Michigan State University
Melatonin, a hormone produced in the human brain, appears to suppress the growth of breast cancer tumors. While treatments based on this new, key discovery are still years away, the results give scientists a key foundation on which to build future research.

Melatonin, a hormone produced in the human brain, appears to suppress the growth of breast cancer tumors.

Researchers at Michigan State University published this finding in the current issue of Genes and Cancer. While treatments based on this key discovery are still years away, the results give scientists a key foundation on which to build future research.

“You can watch bears in the zoo, but you only understand bear behavior by seeing them in the wild,” said David Arnosti, MSU biochemistry professor, director of MSU’s Gene Expression in Development and Disease Initiative and co-author of the study. “Similarly, understanding the expression of genes in their natural environment reveals how they interact in disease settings. That’s what is so special about this work.”

The research team was led by Juliana Lopes, a visiting researcher from Sao Paolo, Brazil. Before the team could test its theory, the scientists had to grow tumors from stem cells, known as “mammospheres,” a method perfected in the laboratory of James Trosko at MSU.

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Mammary Gland Whole Mount Analysis

Mammary whole mounts were prepared using fixed left inguinal mammary glands, stained with carmine alum , and stored at room temperature in methyl salicylate . Imaging of each gland immersed in methyl salicylate was performed with a Nikon SMZ 800 dissecting microscope with an attached Olympus DP70 camera and electronic images were captured using DP control software . Measurements were calibrated with a metric ruler, and the parameters were quantified using Image J software in a blinded manner. Elongation of the ducts into the mammary fat pad and the length of the mammary fat pad were determined by measurement from the center of the lymph node to the farthest terminal duct and to the leading edge of the gland, respectively. Tertiary branching was determined by quantifying the number of tertiary branches per mm2 in three separate distal ductal areas of each gland to determine the mean number of branches per mm2 per mouse.

Address Any Sleep Problems You Have

According to a 2017 study, cisgender women who experience regular sleep difficulties, as well as those who have a prolonged sleep duration have a greater all-cause as well as breast cancer mortality rate.

There are a number of different types of sleep disorders, and these, in turn, are often addressed in different ways. For starters, practicing good sleep hygiene habits can sometimes resolve minor sleep problems.

If problems persist, however, talking to a sleep expert may be in order. We often think of sleep as inconsequential , but given the link between sleep disturbances and survival it might be considered as important as some of the treatments we use to battle the disease.

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Melatonin Mediated Apoptosis In Breast Cancer

More recent research by Proietti et al. has confirmed the work of Cucina by showing that within 3h of treatment with 1nM melatonin, a dramatic decrease in murine double minute 2 , a regulator of p53 ubiquitination, was observed. Down-regulation of MDM2 allowed elevated expression and acetylation of p53, which increased p21 levels, led to decreased cell cycle progression, and promoted p53-mediated apoptosis. Furthermore, those authors reported that melatonin decreased the expression of the survival protein silent mating type information regulation 1 homolog via modulation of the MDM2/murine double minute X -p53 pathway. Both flow cytometry and DNA fragmentation analyses documented a two-phase apoptotic response to melatonin . Early apoptosis appears to be caspase-independent, whereas the later response appears to involve TGF1, caspase-7, caspase-9, PARP cleavage, and a down-regulation of the Bcl-2:Bax ratio. These melatonin-mediated apoptotic responses are even more complex and appear to involve the release of p53 and p73, with p53 being activated in the early response and p73 mediating the caspase-dependent late response.

Cellular And Molecular Actions

Melatonin, an inhibitory agent in breast cancer

Melatonin acts to counteract tumour formation by reducing cell proliferation . In addition, it has antimetastatic properties in cultured MCF-7 cells , which may be due to a reduced chemotactic response and increased expression of cell-surface adhesion molecules . Physiological levels of melatonin have been shown to reduce the invasion of MCF-7 cells, and counteract the increase in oestrogen-induced invasiveness . Melatonin downregulates oestrogen receptor levels in breast cancer cells and blocks ER binding to DNA and transactivation functions . In addition, the induction of differentiation by melatonin has been demonstrated in numerous studies . Highly differentiated cells have a diminished proliferative potential . The myriad of intracellular mechanisms underlying the actions of melatonin are discussed in the following sections and summarised in Figure 1.

Mechanisms underlying the anticancer actions of melatonin

The multiple modes of action of melatonin within the cell make it an excellent candidate hormone for the prevention of cancer in those individuals at risk or for the treatment of cancer in combination with other conventional therapies.

Receptor-dependent actions of melatonin

Recently, microtubules have been implicated in melatonin receptor signalling through a direct effect on Gi activation and also through receptor trafficking and sequestration of MAPK signalling components .

Receptor-independent actions of melatonin

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Ethical Approval Declarations And Consent To Participate

Approval for this study was obtained from the Ethics Committee of Sun Yat-Sen University Cancer Center Health Authority and was carried out according to the ethical standards of the Declaration of Helsinki. The IACUC of Sun Yat-Sen University Cancer Center approved all animal studies, which were performed according to its guidelines. The availability of data and information on the data set used and analyzed in the current study can be provided by the corresponding author upon request.

Study Selection And Data Synthesis

Two systematic searches of published literature were conducted on July 24, 2019 to identify eligible randomized controlled trials and observational or real-world evidence studies reporting any recurrence outcomes for adult patients with HR+/HER2- early BC receiving adjuvant ETs. Ovid MEDLINE®, MEDLINE® In-Process, Embase, and Evidence-Based Medicine Reviews were searched, restricting to articles published in the prior 15 years to reflect contemporary clinical practice, including the widespread approval for the most common AIs . The literature searches were conducted by an information specialist and peer-reviewed using the Peer Review of Electronic Search Strategies Guideline . Recent scientific congresses and relevant systematic reviews or meta-analysis articles were also reviewed. Citation titles and abstracts identified in the literature searches were screened for relevance then further evaluated in full-text form based on the same selection criteria. Literature searches, study selection, data extraction, and quality assessments were performed by duplicate independent reviewers , according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. The review protocol was registered with the International Prospective Register of Systematic Reviews . The full search strategy, eligibility criteria, and list of excluded articles are available in the Supplementary.

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Melatonin: A Regulator Of Epithelialmesenchymal Transition And Metastasis

An early study by Cos et al. noted that the in vitro invasive capacity of ER-positive MCF-7 breast tumor cells was suppressed by melatonin via the regulation of E-cadherin and -integrin. Unfortunately, the luminal A MCF-7 human breast tumor cell line is considered by most to be poorly metastatic . However, using MCF-7 human breast tumor cell clones that overexpressed either the ErbB2/Her2-neu oncogene or the cytokine receptor CXCR4 and MCF-7 cells that serially passaged through nude mice until they developed a metastatic phenotype , Mao et al. demonstrated that melatonin indeed possesses anti-invasive/anti-metastatic action-suppressing cell invasion by 6085% in trans-well/matrigel insert assays. In that study, Mao demonstrated that the anti-invasive actions of melatonin were at least partially mediated by the inhibition of p38 MAPK and matrix metalloproteinases 2 and 9, which are involved in the degradation of the basement membrane and metastatic cell extravasation.

Treatment Effects On Mammary Tumor Development And Metastasis

Understanding Estrogen Receptor-Positive (ER ) Metastatic Breast Cancer (MBC)

Nocturnal melatonin administered with estradiol-progesterone HT significantly reduced the risk of mammary cancer. Besides requiring melatonin supplementation, the type of HT tested is likely important for the observed cancer protection, including the use of natural hormones, low dose HT, and a reduced progesterone dose. For HT alone, the similar cancer risk in old EPT vs. CON mice correlates with studies reporting no increase in breast cancer risk for natural HT . The lack of an HT effect on metastatic incidence in MEPT and EPT mice is likely due to the tumors in Neu mice being ER-/PR-negative and suggests that EPT would not increase tumor aggressiveness or decrease survival in women.

CEE-MPA HT increased the risk of all breast cancer subtypes in the WHI study, with HER2+ cancers having the highest risk . In this mouse model of HER2+ breast cancer, the cancer protective actions of MEPT suggests that the combination therapy may also be effective for other subtypes, such as ER+, PR+, and triple negative breast cancer. But, in ER+ tumors, melatonin, and MEPT may also decrease tumor promotion/growth due to the antiestrogenic actions of melatonin . Further studies in animals and women are needed to evaluate the efficacy of MEPT in other breast cancer subtypes.

Melatonin and HT Cooperate to Reduce Tumor Development

Age Effects on Tumor Development in MEPT and EPT Mice

Melatonin Only Effects on Tumor Development and Metastasis

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Melatonin: A Regulator Of Resistance To Endocrine And Drug Therapy

Resistance to endocrine therapy and chemotherapy are major impediments to the successful treatment of breast cancer . Preclinical and clinical evidence link resistance to anti-estrogen and chemotherapeutic drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Approximately 6075% of breast cancers express ER and PR that are markers and determinants for the use of endocrine therapies, including selective ER modulators, such as TAM . Presently, anywhere from 30 to 50% of patients with ER-positive breast tumors display intrinsic resistance to TAM, whereas most patients that are initially responsive will eventually develop acquired resistance to it . The anthracycline doxorubicin is one of the most frequently used chemotherapeutic agents for patients whose breast tumors are endocrine resistant or metastatic . However, as with endocrine therapies, many cancers are intrinsically resistant to conventional chemotherapeutic agents, and other patients that initially respond well acquire resistance during treatment .


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