High incidence of breast and endometrial neoplasia resembling human Cowdensyndrome in pten(+/-) mice

PTEN is one of the most commonly mutated tumor suppressor genes in human ca ncer. PTEN mutations have been implicated in the development of a variety o f human neoplasia, including high-grade glioblastoma, prostate, breast, end ometrial, and thyroid carcinoma. Germ-line mutations of PTEN cause Cowden's syndrome (CS), a multiple hamartoma condition resulting in increased susce ptibility for the development of cancer. When more than 6 months old, pten( +/-) mice develop a range of tumors, partially resembling the spectrum of n eoplasia observed in CS patients. One-half (32 of 65) of pten(+/-) females developed breast tumors, whereas all (65 of 65) of the females had endometr ial hyperplasia, and there was a high incidence (14 of 65) of endometrial c ancer. Hamartoamous tumors of the gastrointestinal tract, as well as prosta te and adrenal neoplasia, were also frequently observed. Significantly, the spectrum of neoplasia observed in +/- mice partially overlaps with the typ es of tumors frequently detected in CS patients. The majority of tumors in pten(+/-) mice exhibit loss of heterozygosity at the pten locus, which indi cates the importance for loss of PTEN function In tumor formation. Consiste nt with the role of PTEN in negative regulation of PKB/Akt phosphorylation and activity, pten loss of heterozygosity is accompanied by hyperphosphoryl ation of PKB/Akt in tumors. Taken together, our results establish pten(+/-) mice as an excellent animal model system for the investigation of PTEN-rel ated hamartoma syndromes, as well as the role of PTEN in breast and endomet rial carcinogenesis.