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This study aims to detect the impact of pineal gland removal on the incidence of tumor development and to assess the signaling pathways via which exogenous melatonin counteract cancer growth. This goal has been achieved by novel approach for pineal destruction using dental micromotor which validated by melatonin downregulation in blood plasma. Mice were injected sub\u2010cutenously with Ehrlich cells to develop solid tumor as a murine model of breast cancer. The increase at tumor markers carcino embryonic antigen, TNF\u03b1, and nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells was over countered by exogenous melatonin supplementation (20\u2009mg\/kg) daily for 1\u00a0month. The anticancer effects of melatonin were significantly mediated by scavenging H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> and NO and diminishing of lipid peroxidation marker malondialdehyde. The real\u2010time polymerase chain Rx analyses indicated a significant effect of Melatonin in upregulating the expression of miR215, fork head box protein O1 (foxO1), and downregulation of miR96. Flowcytometric analyses indicated a significant effect of melatonin on induction of cell cycle arrest at G1 phase which was further confirmed by Ki67 downregulation. Immunohistochemical analyses indicated the role of melatonin in upregulating P53\u2010dependent apoptosis and downregulating CD44 signaling for survivin, matrix metallo\u2010protein kinase 2, and vascular endothelial growth factor to inhibit cell survival and metastasis. In conclusion, this study sheds the light on M.\/P53\/miR215\/CD44 with an emphasis on M.\/miR96\/\/foxO1 signaling cascades, as a novel pathway of melatonin signaling in adenocarcinoma to diminish cancer cell growth, survival and metastasis.<\/jats:p>","DOI":"10.1002\/biof.1758","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T04:55:23Z","timestamp":1622523323000},"page":"740-753","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Melatonin: A regulator of the interplay between <scp>FoxO1<\/scp>, <scp>miR96,<\/scp> and <scp>miR215<\/scp> signaling to diminish the growth, survival, and metastasis of murine adenocarcinoma"],"prefix":"10.1002","volume":"47","author":[{"given":"Rehab T.","family":"Oshiba","sequence":"first","affiliation":[{"name":"Department of Zoology, Faculty of Science Mansoura University  Mansoura 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