Updated project metadata. Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. Using a co-culture model, we performed an integrated transcriptomic and proteomic analysis of processes induced in ER+ breast cancer cells by close contact with MSCs, but not merely by conditioned media. Computational approaches identified a 52-protein/mRNA ‘signature’ which stratified patients at high risk for relapse, and implicated long-distance intercellular transport via tunneling nanotubes (TNTs) as a means for their ‘acquisition’ by the tumor cell from MSCs. Bioinformatic analyses helped prioritize one gene/protein, CCDC88A/GIV, a multi-functional adapter protein known to drive metastasis. MSCs upregulated GIV in ER+ breast cancer cells through connexin 43-mediated intercellular transport. Stable expression of GIV conferred resistance to clinical anti-estrogen drugs, enhanced tumor dissemination, and recapitulated the 52-gene signature. These data establish a new multi-omic resource for the regulation of breast cancer by MSCs via intercellular transport and validate as proof-of-concept how one transported protein, GIV, orchestrates aggressive disease states.