Cancer progression is a multi-step process requiring cells to acquire specific properties that aid the neoplastic growth. One such property is the ability to survive in the absence of matrix-attachment, a critical necessity for cells to traverse in circulation and seed metastases. Therefore, understanding the signalling mechanisms that protect cells from undergoing death in matrix-deprived condition, termed as anoikis, is important. We have used two systems to study this, one involving experimental transformation model, and another involving cancer cell lines. In the in vitro transformation model system involving the serial introduction of oncogenes, the ability to survive in anchorage-independent condition and generate spheres/colonies was dependent on the presence of the Simian Virus Small T antigen, SV40 ST. We identified that the viral antigen mediates its effects, at least in part, by activating the master metabolic regulator and cellular stress kinase AMP-activated protein kinase (AMPK) leading to maintenance of energy homeostasis. Consistent with this, our lab has previously identified both activation of AMPK upon matrix-deprivation in breast cells, as well as its requirement for survival under these conditions. However, a pathway often associated with survival under matrix-deprivation is the PI3K/Akt pathway. Surprisingly, we observed an AMPK-dependent decrease in Akt activity under conditions of matrix-detachment. Since this was contrary to the general notion, we probed deeper into a possible crosstalk between these two kinases. Our work revealed that AMPK activation in suspension inhibits Akt via upregulation of a known Akt phosphatase, pleckstrin homology domain leucinrich repeat protein phosphatise (PHLPP). We further show that the AMPK-PHLPP-Akt signalling axis is important for anoikis-resistance and metastasis. In addition, our results point to a yet unidentified protumorigenic role of PHLPP in breast cancer progression. With an aim to identify cellular proteins differentially regulated upon AMPK activation in breast cancer cells, we undertook a proteomics approach. Using 2-dimensional gel electrophoresis followed by mass spectrometric analysis, we identified some candidate proteins. We have validated the increase in levels of one of these proteins, annexin A2, in cancer cells upon AMPK activation. In summary, the present study unveils novel oncogenic functions of AMPK in cancer cells under the stress of matrix-deprivation. Furthermore, our results elucidate a double-negative feedback loop between two critical cellular kinases AMPK and Akt, and also identify a novel pro-tumorigenic role of PHLPP in breast cancer. In addition, we identify PHLPP and annexin A2 as novel proteins upregulated by AMPK in cancer cells. Thus, our results begin to identify pathways utilised by cancer cells to aid anchorage-independent growth, a critical step for cancer metastasis. Based on our results, inhibition of AMPK or perturbation of signalling axes involving AMPK, and PHLPP or annexin A2 might be considered as novel therapeutic approaches to combat cancer progression