Breast cancer is the most common cancer in women and the second leading cause of cancer death. Breast cancer is divided into molecular subtypes, with the triple-negative (TNBC) subtype having the worst prognosis. The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway modulates cell proliferation and migration and is dysregulated in ~70% of breast cancers. PIPP is an inositol polyphosphate 5-phosphatase which negatively regulates the PI3K/AKT pathway. Allelic loss of PIPP occurs in ~30% of breast cancers. PIPP mRNA expression is reduced in TNBC and low PIPP mRNA expression correlates with significantly reduced relapse-free and overall survival. PIPP depletion in MDA-MB-231 triple negative breast cancer cells results in increased cell proliferation and anchorage-independent cell growth, but, decreased cell migration (Ooms et al., Cancer Cell 2015). Previous studies have shown that the migration defect in PIPP-deficient cells is mediated by AKT1, however, whether the increase in cell proliferation and anchorage-independent cell growth is AKT isoform-dependent has not been been reported and was investigated here. MDA-MB-231 cells were transduced with non-targeted control, PIPP and/or AKT1, AKT2 or AKT3-specific shRNAs to induce knockdown of PIPP and/or the AKT isoforms. AKT exhibited isoform-specific effects in regulating cell migration, proliferation and anchorage-independent cell growth in PIPP-depleted cells. Screening of a Nanostring nCounter PanCancer Pathways CodeSet identified novel targets that are differentially expressed in PIPP-depleted versus control cells. Quantitative RT-PCR confirmed that the changes in expression of these genes in PIPP-deficient cells was significant and may be regulated by the AKT isoforms. The identified genes play roles in regulating cell migration, proliferation and apoptosis and therefore may be mediators of the cellular phenotypes observed in PIPP-deficient cells. Collectively, the results of this study contribute to the understanding of the mechanisms by which PIPP depletion regulates breast tumour progression, particularly metastasis which accounts for 90% of breast cancer-related deaths.