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Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer.


ABSTRACT: BACKGROUND:Some, but not all, epidemiologic evidence supports a role for cholesterol, the precursor for steroid hormone synthesis, in prostate cancer. Using a PTEN-null transgenic mouse model of prostate cancer, we tested the effect of modifying serum cholesterol levels on prostate tumor development and growth. We hypothesized that serum cholesterol reduction would lower tumor androgens and slow prostate cancer growth. METHODS:PTENloxP/loxP-Cre+ mice consuming ad libitum high fat, high cholesterol diets (40% fat, 1.25% cholesterol) were randomized after weaning to receive the cholesterol uptake inhibitor, ezetimibe (30?mg/kg/day), or no intervention, and sacrificed at 2, 3, or 4 months of age. Serum cholesterol and testosterone were measured by ELISA and intraprostatic androgens by mass spectrometry. Prostate histology was graded, and proliferation and apoptosis in tumor epithelium and stroma was assessed by Ki67 and TUNEL, respectively. RESULTS:Ezetimibe-treated mice had lower serum cholesterol at 4 months (p?=?0.031). Serum cholesterol was positively correlated with prostate weight (p?=?0.033) and tumor epithelial proliferation (p?=?0.069), and negatively correlated with tumor epithelial apoptosis (p?=?0.004). Serum cholesterol was unrelated to body weight (p?=?0.195). Tumor stromal cell proliferation was reduced in the ezetimibe group (p?=?0.010). Increased serum cholesterol at 4 months was associated with elevated intraprostatic DHEA, testosterone, and androstenedione (p?=?0.043, p?=?0.074, p?=?0.031, respectively). However, cholesterol reduction did not significantly affect adenocarcinoma development at 2, 3, or 4 months of age (0, 78, and 100% in ezetimibe-treated vs. 0, 80, and 100% in mice not receiving ezetimibe). CONCLUSIONS:Though serum cholesterol reduction did not significantly affect the rate of adenocarcinoma development in the PTEN-null transgenic mouse model of prostate cancer, it lowered intraprostatic androgens and slowed tumor growth. These findings support a role for serum cholesterol in promoting prostate cancer growth, potentially via enhanced tumor androgen signaling, and may provide new insight into cholesterol-lowering interventions for prostate cancer treatment.

SUBMITTER: Allott EH 

PROVIDER: S-EPMC6026483 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer.

Allott Emma H EH   Masko Elizabeth M EM   Freedland Alexis R AR   Macias Everardo E   Pelton Kristine K   Solomon Keith R KR   Mostaghel Elahe A EA   Thomas George V GV   Pizzo Salvatore V SV   Freeman Michael R MR   Freedland Stephen J SJ  

Prostate cancer and prostatic diseases 20180523 2


<h4>Background</h4>Some, but not all, epidemiologic evidence supports a role for cholesterol, the precursor for steroid hormone synthesis, in prostate cancer. Using a PTEN-null transgenic mouse model of prostate cancer, we tested the effect of modifying serum cholesterol levels on prostate tumor development and growth. We hypothesized that serum cholesterol reduction would lower tumor androgens and slow prostate cancer growth.<h4>Methods</h4>PTEN<sup>loxP/loxP</sup>-Cre<sup>+</sup> mice consumin  ...[more]

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