The Suppressor of Cytokine Signalling (SOCS) family of proteins are critical negative feedback inhibitors of cytokine and growth factor signalling, helping to restore homeostasis and prevent excessive pathological signalling. SOCS5 has been suggested to negatively regulate EGF receptor levels in mammalian cells and has been implicated in EGF receptor driven malignancies. However its precise physiological function and how it might act to regulate signalling pathways has remained poorly characterised. We have utilised mass spectrometry to define the SOCS5 interactome and have identified a number of distinct protein complexes. These analyses have also revealed that the SOCS5 N-terminal region, which is predicted to be largely unstructured and has no known function, to be heavily phosphorylated and we hypothesis that SOCS5 acts as a scaffold to support multiple signalling complexes. Interestingly, many of the identified SOCS5 interacting proteins have been implicated as drivers of aberrant signalling pathways in human breast cancer. Strikingly, in the Polyoma Middle T antigen model of breast cancer, SOCS5-deficient mice exhibit accelerated tumour onset and growth relative to wild-type mice, thus providing the first in vivo evidence that mammalian SOCS5 can act to regulate tumorigenesis. Importantly, analysis of expression databases indicates that SOCS5 is down regulated in a majority of patients with invasive ductal breast carcinoma (TCGA dataset, top 7% under-expressed genes, p=2.53E-23) and may represent an important physiological regulator of breast cancer progression.