The main focus of our study is to assess the anti-cancer activity of cimetidine and vitamin C via combating the tumor supportive role of mast cell mediators (histamine, VEGF, and TNF-α) within the tumor microenvironment and their effect on the protein kinase A(PKA)/insulin receptor substrate-1(IRS-1)/phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase-1 (AKT)/mammalian target of rapamycin (mTOR) cue in Ehrlich induced breast cancer in mice. Here, TNF is linked to cancer.