Breast tumor kinase (Brk) is highly expressed in a majority of human breast cancers, but is absent from normal breast tissues. Enforced Brk expression transforms human mammary epithelial cells in vitro, in part by conferring survival and proliferative advantages. Recently, we discovered that HGF-induced MET receptor signaling (a hypoxic stress-induced signaling pathway commonly associated with triple-negative/basal-type breast cancers) results in robust Brk activation. Notably, Brk mRNA and protein were rapidly upregulated in both normal mammary epithelial cells and breast cancer cells in response to stressful conditions associated with tumor development and progression such as hypoxia, oxidative stress, and low glucose. MET and Brk are co-expressed in invasive breast cancers adapted to survive under hypoxic conditions, due to their constitutive expression of HIF1, a transcription factor mediator of cellular responses to stress. Remarkably, once expressed, Brk activates stress-associated protein kinases such as Erk5 and p38 MAPK, two key effectors of pro-survival/chemoresistance. New data demonstrate that Brk-mediated activation of MAPK family members results in the direct phosphorylation of Sam68, an RNA-binding protein and splicing factor member of the STAR (Signal Transduction Activator of RNA) family that is required for breast cancer cell migration. In RNAi-based studies, knock-down of Brk, ERK5, or Sam68 blocked HGF-induced breast cancer cell migration. Expression of phospho-mutant but not wild-type Sam68 blocked HGF-induced cell migration, indicating an essential role for MAPK-dependent Sam68 phosphorylation. In in vivo studies, WAP-Brk-transgenic mice exhibited heightened stress-activated protein kinase signaling and delayed involution, while aged multi-parious mice developed infrequent mammary tumors. When these mice were crossed with mutant MET receptor knock-in animals, tumor development occurred with shortened latency; early tumors expressed increased levels of Brk and Sik (the mouse homologue of Brk). These data collectively support a model in which tumor-associated hypoxia/nutrient starvation mediates HIF1-induced Brk expression and function, resulting in hyperactivation of MET-driven stress-activated signaling pathways (ERK5 and p38) that lead to increased breast cancer cell survival and migration/invasion. We hypothesize that targeting Brk expression and/or function will inhibit these advanced tumor phenotypes allowing (in the long term) for improved management of triple-negative breast cancer patients. Treatments aimed at cell surface receptors are easily circumvented by activation of downstream effectors or “signaling nodes” in resistant cancers. Brk or Brk-activated signaling molecules (ERK5, p38, Sam68) are potentially druggable targets that could be exploited in breast cancer therapy, thus offering more selective/non-toxic options for patients with deadly basal-type breast cancer who may become resistant to small-molecule inhibitors or antibodies aimed at cell surface receptors (these studies were supported by NIH/NCI grant R01 CA107547).