Abstract The tumor microenvironment (TME), comprised of a heterogeneous population of transformed and non-transformed cells, plays a crucial role in cancer growth. Studies have shown that there is continuous bidirectional communication between cancer cells and the different cell populations within the TME. This communication can either work to promote tumor growth, as seen with carcinoma associated fibroblasts (CAFs), or inhibit tumor growth, as observed with tumor infiltrating lymphoid cells. To date, the majority of research focusing on understanding the role of fibroblasts in the TME has been on CAFs and their ability to enhance tumorigenesis. Although the majority of studies have focused on CAFs, some studies have shown that certain fibroblast populations can antagonize tumor growth. Despite this evidence for an inhibitory role of normal fibroblasts, the precise molecular mechanism by which these cells modulate cancer cell growth has yet to be elucidated. Here, we show that normal mammary fibroblasts (fibroblasts isolated from normal breast tissue) secrete soluble factors that induce caspase mediated cell death in a variety of cancer cell lines. This phenotype was observed in MDA-MB-231s as well as T47D, and BT474 cell lines. Further verification of this phenotype was performed in MDA-MB-231s using Annexin V staining and flow cytometry. When examining the mechanism of apoptotic induction, we observed a substantive increase in the cleavage of caspase 8, evidence that the extrinsic apoptotic pathway is activated. We are currently working to further elucidate the signaling pathways activated in the aforementioned cancer cell lines resulting in the induction of apoptosis by normal mammary fibroblasts. Our research reveals a novel and potentially tumor suppressive function of normal mammary fibroblasts in the tumor microenvironment through secretion of soluble factors that induce apoptosis in cancer cells. Citation Format: Matyas Abel Tsegaye, Mati Nemera, Zachary T. Schafer. Cancer cell apoptosis is induced by soluble factors secreted from normal mammary fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 316.