Macrophage–epithelial interactions play a crucial role in breast cancer progression and metastasis. Tumor associated macrophages (TAMs) provide the tumor microenvironment with multiple inflammatory mediators that stimulate several signaling pathways which participate in survival and growth of cancer cells, thus they have become an attractive target for chemotherapeutic agents. Sulindac Sulfide is one of NSAIDs and its anticancer activity in prevention of tumor incidence and progression has been documented in several types of cancer. The aim of this study was to test the effects of media conditioned by U937 human monocytes (U937-CM) as well as the effect of Sulindac Sulfide on the survival oncogenic expression and apoptosis of MCF-7 cells. The results showed that U937-CM enhanced MCF-7 survival and proliferation through significant increase in Ras expression which resulted in upregulation of anti-apoptotic protein Bcl-2 and down regulation of tumor suppressor Par-4. Sulindac Sulfide treatment inhibited the growth of induced cells by inhibition of Ras expression and its downstream signaling. Suppression of Ras is accompanied by activation of apoptotic machinery through down regulation of Bcl-2 and upregulation of Par-4 that resulted in significant activation of caspase-3.The current data demonstrate that Sulindac Sulfide succeeded in suppressing the paracrine effect of TAMs on breast cancer cells suggesting the promising role in breast cancer treatment.