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Abstract
PTEN mutations are among the most frequent genetic alterations found in human prostate cancers. Our previous works suggest that although precancerous lesions were found in Pten heterozygous mice, cancer progression and metastasis only happened when both alleles of Pten were deleted. To understand the molecular mechanisms underlying the role of PTEN in prostate cancer control, we generated two pairs of isogenic, androgen receptor (AR)-positive prostate epithelial lines from intact conditional Pten knock-out mice that are either heterozygous (PTEN-P2 and -P8) or homozygous (PTEN-CaP2 and PTEN-CaP8) for Pten deletion. Further characterization of these cells showed that loss of the second allele of Pten leads to increased anchorage-independent growth in vitro and tumorigenesis in vivo without obvious structural or numerical chromosome changes based on SKY karyotyping analysis. Despite no prior exposure to hormone ablation therapy, Pten null cells are tumorigenic in both male and female severe combined immunodeficiency mice. Furthermore, knocking down PTEN can convert the androgen-dependent Myc-CaP cell into androgen independence, suggesting that PTEN intrinsically controls androgen responsiveness, a critical step in the development of hormone refractory prostate cancer. Importantly, knocking down AR by shRNA in Pten null cells reverses androgen-independent growth in vitro and partially inhibited tumorigenesis in vivo, indicating that PTEN-controlled prostate tumorigenesis is AR dependent. These cell lines will serve as useful tools for understanding signaling pathways controlled by PTEN and elucidating the molecular mechanisms involved in hormone refractory prostate cancer formation.
Highlights
Prostate cancer is the second leading cause of cancer-related death among North American men [1]
To facilitate our investigation of the molecular mechanisms underlying PTEN-controlled prostate tumorigenesis, we isolated primary prostatic cells from an intact Ptenloxp/loxp;PB-Cre4+ mouse using the same protocol as the generation of Myc-CaP line [15]
One major obstacle to exploring the mechanisms underlying hormone refractory prostate cancer (HRPC) progression is the shortage of good model systems, either in vivo or in vitro, that can truly reflect human prostate cancer progression
Summary
Prostate cancer is the second leading cause of cancer-related death among North American men [1]. Despite improved early detection and initial positive response to androgen ablation therapies, almost all patients eventually develop hormone refractory prostate cancer (HRPC). The molecular mechanisms leading to the progression of HRPC are still poorly understood [2], with. Among genetic alterations frequently found in human prostate cancers, PTEN loss of function has been strongly implicated in prostate cancer development [4, 5]. Similar to the majority of human prostate cancers, Pten null murine prostate cancer initially regress in response to androgen ablation therapy, but subsequently relapse and proliferate in the absence of androgens [7]. The Pten prostate cancer model [7] provides an ideal system for studying the mechanism of HRPC [11]
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