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All authors acknowledge the ethical considerations relevant to this manuscript. Ethical approval for this research was obtained from the Ethics Committee of Urmia University of Medical Sciences under approval code [IR.UMSU.AEC.1401.004]. Mice were maintained under standard housing conditions with a controlled temperature of 22\u00b0C, following a 12-h light\/dark cycle. Food and water were available at all times, and appropriate air conditioning was implemented to minimize potential harm or distress. All necessary measures and precautions were employed to ensure the well-being of the animals. At the conclusion of the experiment, in accordance with IACUC guidelines, all euthanasia procedures for the mice were conducted using carbon dioxide (CO2) gas at a flow rate of 3 L\/min until respiration ceased\n                      62\n                      . Prior to this procedure, the animal received anesthesia to minimize distress, which involved administering a mixture of ketamine (80 mg\/kg) and xylazine (5 mg\/kg) via intraperitoneal injection. Euthanasia was subsequently performed using CO\u2082 asphyxiation, followed by the cervical dislocation method, which involved placing a pen directly behind the ears at the base of the skull and, while lifting the base of the tail, dislocating the cervical vertebrae. In this study, female BALB\/c mice, weighing between 21 and 23 g and aged 6\u20138 weeks, were obtained from the Pasteur Institute in Tehran, Iran. Upon reaching the logarithmic growth phase, 4T1 cell lines were trypsinized (using Gibco), resuspended, and a suspension containing 1\u2009\u00d7\u200910\n                      5\n                      4T1 cells in 100 \u03bcL of sterile phosphate-buffered saline (PBS) was injected into the mammary fat pad of the mice. Eight days post-implantation, the mice were evaluated for tumor growth and were randomly assigned to treatment and control groups. The experimental groups consisted of eight categories: Control or Untreated, Alp (Alpelisib treated), TRPM8 ant (TRPM8 antagonist treated), CB1 ant (CB1 antagonist treated), Alp\/CB1 ant (Alpelisib & CB1 antagonist treated), TRPM8\/CB1 ant (TRPM8 & CB1 antagonist treated), Alp\/TRPM8 ant (Alpelisib & TRPM8 antagonist treated), and Alp\/CB1\/TRPM8 ant (Alpelisib & CB1 & TRPM8 antagonist treated), with n\u2009=\u20095 mice in each group. In total, n\u2009=\u200950 mice were utilized for tumor induction, resulting in n\u2009=\u20094\u20135 mice in each experimental group. Mice that did not develop a tumor mass or exhibited a tumor mass significantly larger than the others by day 8 of induction were excluded from the study. Additionally, 4\u20135 mice were randomly allocated to each cage (Large cage Size (W\u2009\u00d7\u2009L\u2009\u00d7\u2009H), 7.5\u2033\u2009\u00d7\u200911.75\u2033\u2009\u00d7\u20095\u2033) for each experimental group.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"16876"}}