Kisspeptin KiSS1 , a gene product of KiSS1 , is known to regulate the onset of puberty and to suppress cancer metastasis 20 , KiSS1 expression levels are increased in primary breast cancer lesions but reduced in metastatic lesions 22 — 25 , suggesting that KiSS1 may serve pleiotropic functions during breast cancer development and metastasis While it was revealed that melatonin regulates KiSS1 expression in the hypothalamus in the brain 26 , 27 , an association between melatonin and KiSS1 in cancer has not been identified.
While 1 mM melatonin treatment inhibited metastatic functions, including migration and invasion in triple-negative MDA-MB breast cancer cell lines, the pharmacological concentration of melatonin also reduced the cell viability and caused apoptosis 28 — In addition, physiological concentrations of melatonin only reduced the viabilities of less invasive, non-triple-negative breast cancer cells 28 , 31 , 32 , which may be due to different MT1 expression levels in less or highly invasive breast cancer cells Therefore, whether melatonin directly inhibits the invasion of highly metastatic triple-negative breast cancer cells remains unclear.
GATA3 expression patterns in breast cancer appear to correlate with the expression patterns of estrogen receptors and progesterone receptors 39 , Therefore, less invasive, hormone-positive breast cancer is likely to express high levels of GATA3 40 , Inversely, patients with highly invasive triple-negative breast cancer may present with low levels of GATA3, which appears to be maintained during metastasis 41 , The aim of the present study was to understand the function of melatonin in triple-negative breast cancer cells.
In addition, melatonin-induced KiSS1 expression prolonged its inhibition of metastatic abilities, as confirmed by promoter assays and KiSS1 silencing in the cells. It was also revealed that melatonin increased the expression levels and activated transcriptional activity of GATA3 for KiSS1 expression. Therefore, the results of the present study suggested that melatonin prolongs the inhibitory effect on breast cancer metastasis by activating GATA3-mediated KiSS1 expression. Luciferase assays were performed in triplicate, and three times independently.
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PCRs were performed using a LightCycler Instrument II, and relative quantifications were automatically conducted by the efficiency method 43 , 44 in LightCycler software 1. The membranes were then incubated in secondary antibodies conjugated to horseradish peroxidase anti-rabbit, cat no.
Band detection was performed using LumiGLO chemiluminescent reagent and peroxidase cat no. Western blot experiments were replicated at least three times independently.
For relative quantifications, ImageJ software version 1. Experiments were performed in quadrate and independently repeated in triplicate. Experiments were performed in triplicate. Non-treated cells were used as a control in this migration assay. The cells in the upper chamber were removed with a swab, and cells that had invaded through the Matrigel were stained with 0. Non-treated cells were used as a control. The migration and invasion assays were observed using a Zeizz Axiovert inverted microscope and images were analyzed using Zen software version 3.
A total of 4 fields were randomly selected and the invaded cells were counted.
Melatonin-induced KiSS1 expression inhibits triple-negative breast cancer cell invasiveness
In the overexpression analysis, the pcDNA empty vector was used as the control plasmid. To examine the effect of melatonin on the proliferation of triple-negative MDA-MB and HCC breast cancer cells, the cells were treated with melatonin at different concentrations 0, 1, 10, 10 2 , 10 3 and 10 4 nM for 48 h. Data from the cell proliferation assays demonstrated that melatonin did not affect the proliferation of triple-negative breast cancer cells Fig. Melatonin inhibits metastasis in triple-negative breast cancer cells.
Migrated cells on the wounding regions were counted. Next, whether melatonin affects triple-negative breast cancer cell migration and invasion was examined. The results of the present study revealed that melatonin inhibited the migration and invasion of triple-negative breast cancer cells. This result was consistent with a previous study Nevertheless, the mechanisms by which the inhibitory effect of melatonin is prolonged were not investigated.
It was assumed that melatonin may maintain its inhibitory effect by inducing the production of anti-invasive proteins. Therefore, the effect of conditional medium from the cells treated with melatonin on the invasiveness of the breast cancer cell lines was examined.
Melatonin induces KiSS1 production. MDA-MB cells were treated with conditioned medium for another 24 h and then subjected to Matrigel invasion assay. The invading cells were counted.
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KiSS1, kisspeptin. KiSS1 is known to inhibit cancer cell migration and invasion, resulting in a suppression of cancer metastases Thus, whether melatonin affects KiSS1 expression in triple-negative breast cancer cells was examined. To examine whether melatonin affected KiSS1 expression at the transcriptional level, luciferase assays were performed in T cells transfected with different KiSS1-luc constructs.
Triple negative breast cancer grade 3 | Cancer Chat
When this region was analyzed in silico , the GATA binding site was identified. Therefore, these data indicated that melatonin activated KiSS1 expression at a transcriptional level. The illustration represents a region for chromatin immunoprecipitation. KiSS1 knockdown was confirmed by western blotting. Whether melatonin-induced KiSS1 expression is required for the inhibition of the invasiveness was then examined.
The present study revealed how melatonin prolongs its inhibitory effect on the invasiveness of triple-negative breast cancer cells. Consequently, KiSS1 maintained a melatonin-induced inhibitory effect. MT1 deficiency in metastatic breast cancer cells may explain why melatonin fails to inhibit proliferation However, previous studies have demonstrated that melatonin inhibited the metastatic abilities of MDA-MB breast cancer cells by inhibiting either Rho-associated protein kinase 1 or p38 mitogen-activated protein kinases 31 , 32 , Likewise, the results of the present study revealed that melatonin inhibited the invasiveness of triple-negative breast cancer cells with no effect on proliferation.
In addition, melatonin was revealed to maintain its inhibitory effect by inducing KiSS1 expression. Likewise, KiSS1 silencing prevented melatonin-induced inhibition of invasiveness. KiSS1 is known to inhibit the metastatic abilities of cancer cells including the invasiveness Thus, KiSS1 appears to prolong the inhibitory effect of melatonin on the invasiveness of breast cancer cells via GATA3 transcriptional activation. The present study demonstrated that melatonin promoted KiSS1 expression in triple-negative breast cancer cells. As a disruption of light cycles increases the risk of breast cancer 13 , 47 , 48 , it is plausible that melatonin and KiSS1 may exhibit similar expression patterns in breast cancer.
Melatonin has been revealed to regulate circadian rhythms by inhibiting KiSS1 expression in the brain of rodents However, melatonin induces KiSS1 expression in fish, and vice versa 49 , Therefore, the mechanisms that result in the different effects of melatonin on KiSS1 expression in different experimental conditions, including animal models, remain unknown. In conclusion, the present study suggested that melatonin prolongs its anti-metastatic effect by activating GATA3-mediated KiSS1 expression.
While the effect of melatonin on breast cancer has been examined, to the best of our knowledge the present study is the first to reveal the effect of melatonin on triple-negative breast cancer cells.
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J Neurosci. J Biol Chem. J Neuroendocrinol. Nat Rev Neurosci. Mol Cell Endocrinol. Sleep Med Rev. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. In the epithelial cells of the human breast, both growth inhibition and growth stimulation by estradiol were observed depending on the rate and activity of ERs and GFRs. In malignancies, a dynamic inverse relationship was revealed between the expressions of GFRs and membrane-associated ERs. The recognition of counteractions between GFRs and ERs may explain how a successful ER blockage by tamoxifen treatment may induce overwhelming GFR predominance, resulting in fatal outcome of the disease.
In summary, pregnancy-associated high estrogen level is protective against the initiation and progression of all breast cancer subtypes; however, the intensity of this defense strongly depends on the molecular subtype of the tumors: the higher the ER expression of the cancer, the stronger the tumor-suppressive effect of estrogen. High-dose estrogen was administered as endocrine therapy for postmenopausal women with breast cancer prior to the introduction of tamoxifen, the first antiestrogenic compound, in the s.
Following these observations, the use of estrogen therapy was almost completely abandoned. Tamoxifen was the first compound designated as an antiestrogen, or, more exactly, a selective ER modulator that binds to ERs so as to inhibit their signaling pathways. Another group of antiestrogens is known as aromatase inhibitors. These compounds prevent the activity of P aromatase, which converts steroid precursors and androgens to estrogen, causing estrogen deprivation in both healthy tissues and tumors.
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Introduction of aromatase inhibitors successfully avoided the presumed estrogen agonist activities of selective ER modulators; however, toxicity aside, their anticancer effects were not reliable. A number of authors consider that estrogen may become an apoptotic trigger instead of a survival signal for tumor cells after many years of estrogen deprivation.
Molecular classification and molecular forecasting of breast cancer: ready for clinical application?