The chemotherapeutic treatment of breast cancer relies on blood vessels to reach the tumour mass. Neo-angiogenesis in tumours is caused by low oxygen levels (hypoxia) and results in poorly functioning vessels which are commonly leaky and obstructed. This hinders efficient chemotherapeutic drug delivery to the tumour, resulting in low anti-tumour efficacy and severe side effects of the treatment. Here, we present that the knockout of the Siah2 E3 ubiquitin ligases, the apical regulator of the hypoxic pathway, results in a normalization of breast cancer blood vessels in spontaneous and syngeneic, orthotopic models. This vessel normalization is characterized by increased blood perfusion, pericyte-covered vessels, reduced tumour hypoxia and an increased number of functional vessels. Exploiting this vascular phenotype, we demonstrate that a chemotherapeutic drug, Doxorubicin, can be delivered at a higher concentration into the tumours, resulting in higher anti-cancer efficacies and prolonged survival. Therefore, vascular normalization caused by blockade of Siah function is a novel way to increase anti-cancer efficacies of current chemotherapeutic drugs or reduce the side effects of these drugs by enabling usage of lower amounts of the chemotherapeutics to obtain similar efficacies.