Breast cancer is the most common cancer type amongst women in the United States and will account for approximately 7% of all cancer-related deaths each year. For most breast cancer patients, conventional genotoxic therapy is the standard of the care. Unfortunately, as breast cancer progresses it becomes treatment resistant and incurable. Therefore, understanding mechanisms of treatment response and resistance are of paramount importance. Stromal communication with cancer cells is a major determinant of progression and treatment response. We show that stromal and breast cancer (BrCa) cells utilize paracrine and juxtacrine signaling to drive progression and conventional therapy resistance. Upon heterotypic interaction, exosomes are unidirectionally transferred from stromal to breast cancer cells. Breast cancer cells stimulate stromal cell upregulation of RNA polymerase III through activation of stromal NOTCH1 and MYC. This results in a subsequent increase in stromal 5’triphosphate RN7SL1, an SRP RNA, in exosomes. Unlike cytoplasmic RN7SL1 that is shielded by RNA binding proteins (RBPs), RN7SL1 in exosomes produced after breast cancer cell interaction lack RBPs like SRP9 and SRP14. Consequently, unshielded stromal RN7SL1 in exosomes, which is also found in cancer patients, is transferred to breast cancer cells to stimulate the pattern recognition receptor RIG-I and activate STAT1-dependent anti-viral signaling. In parallel, stromal cells also activate NOTCH3 on breast cancer cells. The paracrine anti-viral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy resistant tumor-initiating cells. Primary human and mouse breast cancer analysis support the role of anti-viral and NOTCH3 pathway crosstalk in maximal activation of NOTCH signaling and stromal-mediated resistance. Stromal-mediated therapy resistance can be overcome by combination of conventional therapy with γ-secretase inhibitors. Thus, RBPs shield endogenous POL3-driven RNA from RIG-I, a process circumvented when breast cancer cells coerce stromal cells to propagate anti-viral signaling through exosomes. Anti-viral and NOTCH3 signaling then converge to enhance tumor growth, metastasis, and therapy resistance.