PTEN Deficiency Is Fully Penetrant for Prostate Adenocarcinoma in C57BL/6 Mice via mTOR-Dependent Growth

Abstract

The tumor suppressor phosphatase and tensin homolog (PTEN) is frequently involved in human prostate carcinoma. PTEN is therefore an attractive target for the development of preclinical animal models. Prostate intraepithelial neoplasia lesions develop in mice with Pten heterozygosity, but disease progression has been reported only in combination with either other tumor suppressor gene alterations or the conditional inactivation of both Pten alleles in prostate epithelial cells. We report that on a C57BL/6 background, in contrast to previous studies on mixed 129 genetic backgrounds, Pten locus heterozygosity is fully penetrant for the development of prostate adenocarcinoma. Grossly observable tumors were detected at 6 months of age, and, by 10 to 12 months, 100% of examined mice developed adenocarcinoma of the anterior prostate. Furthermore, double heterozygotes carrying both Pten and Tsc2-null alleles showed no increase relative to Pten ؉/؊ heterozygotes in either lesion development or progression. Lesions in both Pten ؉/؊ ; Tsc2 ؉/؊ , and Pten ؉/؊ mice exhibited loss of PTEN expression and activation of PI3K signaling. PI3K activation occurred early in prostate intraepithelial neoplasia lesion formation in these animals , consistent with loss of PTEN function , and contributed to the etiology of tumors that developed in Pten ؉/؊ mice. Furthermore , prostate lesion growth in Pten ؉/؊ mice was dependent on mTOR , as evidenced by a reduction in both phospho-S6 levels and proliferative index after rapamycin treatment.

In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

“…8,9 Moreover, PTEN-negative tumors are resistant to androgen deprivation but exhibit enhanced sensitivity to treatments with PI3 kinase and mTORC1 inhibitors, thereby demonstrating a dependency for the mTORC1 pathway for growth in conditions of low androgen circulating levels. [8][9][10] Similar findings have been observed using the human LNCaP xenograft model, 11 which respond better to a combined treatment of castration and rapamycin than to the each of the treatments alone. 12 In contrast to these findings, phase II clinical trials have shown little effects of the rapamycin analogue RAD001 as an addon therapy to the AR antagonist bicalutamide for the treatment of castration-resistant prostate tumors in human patients.…”

Inhibition of Mammalian Target of Rapamycin With Rapamycin Reverses Hypertrophic Cardiomyopathy in Mice With Cardiomyocyte-Specific Knockout of PTEN

“…10 PTEN deficiency is capable of promoting hyperactivation of mTOR in animal models and patients. 11,12 It is widely conceived that mTOR orchestrates cardiac hypertrophy given its role in governing protein synthesis. 13 Aberrant activation of mTOR has been shown to contribute to the onset and development of cardiac hypertrophy.…”

Phosphorylation of Ribosomal Protein S6 Attenuates DNA Damage and Tumor Suppression during Development of Pancreatic Cancer

“…Rapamycin (1.5 mg/100 mL caboxymethyl cellulose) was injected at 0.3 mg/kg on the first day after DMBA implantation and then 0.15 mg/kg every other day for 1 month. This low dose of rapamycin used was selected to minimize potential nonspecific effect and was based on several articles that used a similar protocol (33)(34)(35).…”