The association with the TNFa/TGFb-related pathways is brought about through the interactions of NASP, RPS10, HSPA8, and HSPA1B with TRAF6, a key factor acting upon the TNFa/TGFb signaling axis. In the MB-435-based network 2, the involvement of the TNFa/TGFb signaling axis is associated with RPSA, GLO1, and CTSD interactions with TNF as well as CTSD and KRT1 interactions with TGFB1. Finally, in the 17-gene brain metastasis signature associated networks 1 and 2, the involvement of the TNFa/TGFb signaling axis is evoked via the interactions of 2 proteins with TGFb as well as by interactions between PTGS2, HBEGF, and TNFSF10 in network 1 ; whereas interactions of PLOD2 and ANGPTL4 with TGFB1 as well as LAMA4, B4GALT6, and SEPP1 with TNF bring up TNFa/TGFb signaling axis in network 2. Likewise, the involvement of the NFKB pathway is brought about by the interactions of HSPA8 and XRCC6 with NFKBIA in MB-231-based networks 1 and 2, whereas in MB-435-based network 1 and 17-gene brain metastasis signature associated network 1, the NFKB pathway involvement is evoked by PRDX4 and VIM, or PELI1 and RARRES3 interactions with NFKB complex. Similarly, the TP53 pathway in MB-231-based network 1 is brought about by HSPA8, HNRNPA2B1, and XRCC6 interactions with TP53, while in MB-435-based network 2 it is associated with TP53 interactions with RAD50, RPSA, and CTSD. All these examples demonstrate that, whereas highly related signaling networks involving similar major signal transduction pathways are associated with brain colonization by cancer cell lines and primary tumors, different cancer cells may exploit distinct avenues to achieve the same goal, i.e. engage signaling pathways and networks essential for a successful organ-specific colonization of the brain by metastatic breast carcinoma cells. The availability of multiple alternative routes for activating these pathways means that, when a single protein or gene is targeted therapeutically to block a certain metastasis-associated pathway, the success is likely to be transient. Due to their robustness and plasticity, metastatic cancer cells will adapt to changing conditions and use available alternative routes to circumvent the roadblocks imposed by therapeutic interventions and NVP-BKM120 activate signaling network required for them to continue thriving in distant organ milieu. Thus, creating new treatment paradigms targeting these networks in their entirety, rather than single proteins, could be necessary for controlling and treating efficiently breast carcinoma brain metastases. Cellular migration has been an intriguing phenomenon for many years. From wound healing and immune response of mammalian cells, to chemotaxing bacteria and amoeba, living cells exhibit a variety of motility abilities. Most motile cells attempt to follow external directional signals while moving in a complex environment.