Specific diets can affect the risk and progression of prostate cancer (PCa). However, the interplay between diet and genetic alterations remains ill defined. Here we show that progression of PCa that is driven by Pten loss is mostly unresponsive to a high fat diet; however, in the absence of protein tyrosine phosphatase Ptpn1 (which encodes PTP1B) mice that are fed a high fat diet develop a highly invasive disease that is characterized by increased cell proliferation and Akt activation. Together with the finding that prostate-specific PTP1B overexpression does not initiate PCa by itself, we conclude that PTP1B act as an environment-dependent tumor suppressor in the context of Pten-null prostate tumors. PTP1B is a validated therapeutic target at the crossroad of metabolism (diabetes, obesity) and cancer (breast), and is currently being investigated in clinical trials. Due to PTP1B's nutrient sensing capabilities, we suggest that a careful monitoring of the balance between improving metabolic syndrome and promoting oncogenic effects under particular diets be pursued when using PTP1B-targeted therapeutics.