Melatonin effect on the modulation of miRNAs involved in metastasis of breast cancer

Abstract

Breast cancer is the most common tumor type in women, and the leading cause of death of these patients is tumor progression and metastasis. MicroRNAs (miRNAs) are small non-coding mRNA molecules that play a key role in gene regulation. Recent studies have shown that miRNAs are directly involved in the initiation and progression of several tumor types, including breast cancer. Several miRNAs have been described suppressors or as promoters of metastases, may be associated with tumor growth and metastasis or inhibiting the signaling resulting in a significant suppression of cell invasion. Melatonin, a hormone secreted by the pineal gland, has presented oncostatic and antimetastatic effects by reducing the ability of migration and invasion in tumor cells. In addition, a recent study demonstrated that melatonin can modulate the expression of miRNAs in breast cancer promoting an antiproliferative action. The objective of this study is to evaluate the potential therapeutic value of melatonin to modulate miRNAs in breast cancer, using in vitro and in vivo metastasis study. In silico analysis will be conducted for selection of miRNAs involved with the development of metastasis in breast cancer. The differential expression of these miRNAs will be assessed by PCR-Array using cell lines MDA- MB-231 treated or not with melatonin and MCF-10A, the results will be validated by silencing or overexpression of these miRNAs by gene expression, protein analysis and invasiveness and migration evaluation. To verify the modulatory action of melatonin on miRNAs candidates in an in vivo study, athymic nude mice will receive an intravenous injection of tumor cells to the development of lung metastasis, and the action of candidate miRNAs and their target genes will be proved by using agents will promote their silencing or overexpression associated with melatonin treatment. The results achieved will determine the possible relationship of melatonin with miRNAs involved in the formation of metastasis and thus establish potential therapeutic protocols for control of this cellular event.