The identification of genes essential for the survival of the normal mammary epithelium may yield novel therapeutic targets for the treatment of a wide range of breast tumours. Using N-ethyl-N-nitrosourea (ENU) mutagenesis in a forward genetic screen we have identified a dominant mutant mouse line (Jersey) that displayed reduced mammary epithelial viability. Phenotypic characterisation showed that Jer/Jer homozygous mutants had defective mammary gland development characterised by poor alveolar organisation and luminal cell detachment which resulted in complete failure of lactation and pup mortality by 4 days post-partum (dpp). Epithelial cells in Jer/Jer mammary glands displayed reduced proliferation and fewer mammary progenitor cells at mid-pregnancy as well as increased apoptosis at 2 days post partum. Mammary glands produced by transplanting Jer/Jer mammary epithelium into cleared WT mammary fat pads showed a similar defect indicating that the mutation was mammary cell autonomous. No other defects were observed in other organs and suggested the Jersey defect was specific to the mammary epithelium. Enforced expression of the Jersey mutation in T47D human breast cancer cell lines resulted in loss of adhesion, apoptosis and altered expression of JNK and NF-kB pathway members. Homozygous Jersey mutants carrying the polyoma middle T antigen (PyMT) oncogene developed mammary tumours that progressed more rapidly than those in control mice. Furthermore, high expression of Jersey and its signalling partners was correlated with poor overall survival and metastasis free survival in human breast cancers (Oncomine™ (Compendia Bioscience, Ann Arbor, MI). This work defines a previously unknown role of Jersey in mammary development and carcinogenesis. Since the Jersey mouse is otherwise normal this information may be exploited to provide a new therapeutic target for breast cancer offering low toxicity.