Phosphoinositide signals interact with a host of intracellular effectors to regulate cell proliferation and apoptosis, cell migration and metatasis. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway promotes cell proliferation and survival, and is hyper-activated by a variety of mechanisms in up to 70% of human breast cancers. The class I PI3K generates the lipid signal PI(3,4,5)P3 at the plasma membrane in response to growth factor receptor activation. This phosphoinositide is degraded by the tumor suppressor PTEN, by hydrolysis of the 3-position phosphate on the inositol head group, terminating its signaling. In addition inositol polyphosphate 5-phosphatases degrade PI(3,4,5)P3 to form a new signal, PI(3,4)P2. Both PI(3,4,5)P3 and PI(3,4)P2 are required for maximal activation of the serine threonine kinase AKT. INPP4B degrades PtdIns(3,4)P2 to form PtdIns(3)P and thereby inhibits PI3K-dependent AKT signalling in breast and other cancers. Recently, INPP4B was identified a putative tumour suppressor in breast and ovarian cancer. Reduced INPP4B expression is observed in basal-like and triple negative breast cancers associated with poor long-term outcome. Paradoxically increased INPP4B expression has been recently identified in human laryngeal cancer, acute myeloid leukemia (AML), colon cancer and melanoma, and in some contexts mediates therapeutic resistance, although the molecular mechanisms remain unclear. Here we have characterized INPP4B mRNA and protein expression in primary human breast cancer, and examined the correlation between INPP4B expression, molecular subtype and patient survival revealing increased expression in a subset of luminal breast cancers, associated with reduced long term outcome. Ectopic INPP4B expression in ER+ve cell lines increased anchorage independent cell growth, in a phosphatase-dependent manner, through enhanced cell proliferation, despite suppression of AKT signaling. Whole cell proteomic and immunoprecipitation-mass spectrometry analyses have revealed a previously unreported function for INPP4B, dependent both on its PI(3,4)P2 4-phosphatase activity and on protein:protein interaction, but independent of INPP4B regulation of AKT signalling. Here, we propose a novel signalling role for INPP4B in breast cancer cell proliferation, which demonstrates the complex role INPP4B plays in the regulation of breast cancer progression.