PTEN is one of the most commonly mutated tumor suppressor genes in human cancer. PTEN mutations have been implicated in the development of a variety of human neoplasia, including high-grade glioblastoma, prostate, breast, endometrial, and thyroid carcinoma. Germ-line mutations of PTEN cause Cowden's syndrome (CS), a multiple hamartoma condition resulting in increased susceptibility for the development of cancer. When more than 6 months old, pten+/- mice develop a range of tumors, partially resembling the spectrum of neoplasia observed in CS patients. One-half (32 of 65) of pten+/- females developed breast tumors, whereas all (65 of 65) of the females had endometrial hyperplasia, and there was a high incidence (14 of 65) of endometrial cancer. Hamartoamous tumors of the gastrointestinal tract, as well as prostate and adrenal neoplasia, were also frequently observed. Significantly, the spectrum of neoplasia observed in pten+/- mice partially overlaps with the types of tumors frequently detected in CS patients. The majority of tumors in pten+/- mice exhibit loss of heterozygosity at the pten locus, which indicates the importance for loss of PTEN function in tumor formation. Consistent with the role of PTEN in negative regulation of PKB/Akt phosphorylation and activity, pten loss of heterozygosity is accompanied by hyperphosphorylation of PKB/Akt in tumors. Taken together, our results establish pten+/- mice as an excellent animal model system for the investigation of PTEN-related hamartoma syndromes, as well as the role of PTEN in breast and endometrial carcinogenesis.