Melatonin Inhibits the Metastatic Ability of HER2/neu-negative Breast Cancer Cells by Suppressing Epithelial-to-Mesenchymal Transition (EMT)-Associated Genes with Predictive and Prognostic Relevance

Abstract

Background: Over 50%of cancer metastasis from breast cancer develops bonemetastases that are not sensitive to hormonal therapy, radiation therapy, or chemotherapy. The epithelial-to-mesenchymal transition (EMT) genetic program is implicated as a significant contributor to breast cancer progression. As such, targeting the EMTrepresents an important therapeutic strategy for preventing or treating breast cancer metastasis.Melatonin is hormone whichmediates photoperiodicity inmammals, inhibits cerebellar nitric oxide synthetase, peroxynitrite scavenger. Melatonin has complex effects on apoptotic pathways, inhibiting apoptosis in immune cells and neurons but enhancing apoptotic cell death of cancer cells. Inhibits proliferation/metastasis of breast cancer cells by inhibiting estrogen receptor action.Melatonin is characterized with variety of properties such as antioxidant, autocoid, paracoid and hormonal properties, as well as anti- inflammatory and anti-apoptotic properties. Melatonin is implicated in the regulation of seasonal reproduction, energy metabolism and thermoregulation inmammals.Melatonin plays a vital role in the lessening of neonatal hypoxia-ischemia (HI) induced endoplasmic reticulum (ER) stress and conserves sirtuin 1 (SIRT-1) expression. In this study,we investigated the molecularmechanism by which melatonin represses themetastatic potential of HER2/neu-negative breast cancer. Methods: The effects of melatonin on cell migration and invasion were determined by transwell migration assay and Matrigel invasion assay. Expressions of EMT-related genes were determined by an EMT PCR Array and a quantitative RT-PCR. The prognostic relevance of melatonin's modulation of EMT-related genes in breast cancer was evaluated using Kaplan-Meier survival analysis. Results:Melatonin exerted inhibitory effects on the migratory and invasive abilities of highly metastatic breast cancer cells. These inhibitory effects of melatonin resulted in significant repression of a panel of mesenchymal genes that regulate the developmentalEMT.Among EMT-related genes downregulated bymelatonin, highNODAL, Snail and BMP7 gene expressions ofmetastatic breast cancer tissueswere associatedwith shorter survival of breast cancer patients and provide potential therapeutic interventions. Conclusions: We concluded that melatonin should be developed as a pharmacological agent for use in combination with other anticancer drug for treating metastatic HER2/ neu-negative breast cancer.