DNA Damage incites the tumour suppressor p53 to dynamically respond and instigate either a temporary cellular arrest to allow repair, or a permanent growth inhibition. p53 functions to restrict the perpetration of genetic aberrations into subsequent generations of cells. The potency of the p53 response necessitates its rapid containment post demand, to prevent excessive inhibition of vital cellular activities. p53 is strictly regulated by the Hdm proteins: Hdm2 and Hdmx. A mechanism selected in some cancers for breaking p53 tumour suppression is to elevate the Hdm proteins. we have identified in human luminal breast cancer (BrCa) TMAs elevated expression levels of Hdmx at high frequency. Rationalising that intervention to reduce Hdmx levels will re-activate p53 in breast cancer cells, we inducibly knocked down Hdmx in selected BrCa lines. In vitro growth of lumincal BrCa cells was significantly inhibited by Hdmx knock down (KD). Importantly, KD of Hdmx restricted the growth of luminal BrCa xenografts in NSG mice.These studies demonstrate a proof of principle for Hdmx as a rationale target for luminal breast cancer therapy with potential for potentiation in combination with targeting Hdm2.