Abstract Anti-inflammatory TGFβ and pro-inflammatory TNFα/IL1β cytokines are among the major cytokines in tumor microenvironment that drive cancer progression and metastasis. Published studies implicate TGFβ-activated protein kinase TAK1 as an important mediator in cytokine-driven tumor invasion and metastasis. TAK1 is an ubiquitin-dependent protein kinase that can activate NFκB and MAPK signaling cascades. This study addressed several foremost questions such as a) what signaling cascade is activated by the cytokine crosstalk and what are major transducers and effectors of this crosstalk; b) whether a crosstalk is associated with a specific genetics or cell type, for example a specific molecular subtype of breast cancer. Molecular profiling study identified a TAK1-dependent molecular signature and revealed a close association of the TAK1 molecular signature with triple-negative breast cancers. The cytokines synergistically stimulated expression of a set of pro-invasive and pro-metastatic molecules including matrix metalloproteinase 9 (MMP9). shRNA screening study identified specific molecular transducers of TAK1 that mediate MMP9 expression and cell motility. In particular, our study found an essential role of RELA but not NFKB2 in regulation of MMP9. Addressing a signaling crosstalk, we found that TGFβ and TNFα robustly activated a significant level of canonical signaling via SMADs and RELA/NFkB, respectively, but neither of these cytokines cross-talked to stimulate canonical transducers for a respective cytokine. Instead, TGFβ and TNFα synergized in activation of MAPK signaling and up-regulation of specific transcription targets of the cytokine pathways. In summary, anti-inflammatory TGFβ and pro-inflammatory TNFα cytokines synergize in stimulation of tumor invasion and metastatic potential by cooperating in TAK1-mediated regulation of MAPK signaling and expression of target genes. A TAK1 molecular signature is associated with triple-negative breast cancers. Citation Format: Andrei V. Bakin, Michelle Limoge, Amy Beattie. Cross-talk of the cytokine pathways in cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 36. doi:10.1158/1538-7445.AM2015-36