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Conditional Deletion of the Pten Gene in the Mouse Prostate Induces Prostatic Intraepithelial Neoplasms at Early Ages but a Slow Progression to Prostate Tumors Introduction Prostate cancer affects about 2,276,000 men in the United States and is the most common non-cutaneous malignancy among males in the Western world. The phosphatidylinositol (3,4,5)-phosphate-ki-nase (PI3K) signaling pathway plays a critical role in human tumorigenesis, including prostate cancer [1]. The phosphatase and tensin homolog chromosome 10 (PTEN) is a tumor suppressor[2,3] and functions as a negative regulator of the PI3K pathway by blocking the activation of the kinase Akt/PKB [4,5]. PTEN is one of the most commonly mutated and/or deleted tumor suppressors in human malignancies. Somatic mutations of PTEN have been detected at high frequency in many sporadic cancers, including glioblastoma, endometrial cancer, and prostate cancer [6].Complete PTEN inactivation has been found in 15% of primary prostate tumors, and in up to 60% of prostate cancer metastases[7,8,9]. The biological significance of Pten has been carefully characterized in numerous mouse models. Pten null (Pten2/2) mice are embryonic lethal [10]. Pten heterozygous (Pten+/2) mice are viable and develop tumors in a variety of organs, including the breast,thyroid, endometrium, and prostate [11,12,13]. Biallelic conditional knockout of Pten in mice induces tumor development in specific tissues [14]. Mouse models with conditional Pten deletion in the prostate have been developed in the past decade [15,16,17].In particular, deletion of Pten in the mouse prostate using probasin- Cre induces oncogenic transformation [15]. In mice, loss of one allele of Pten is associated with the development of high-grade prostatic intraepithelial neoplasia (PIN) and the loss of both alleles of Pten results in invasive prostate cancer that metastasizes to lymph nodes and the lung [15]. Pten null tumors in Pten LoxP/LoxP :PB-Cre4 mice can further devel