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.
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Funding
EHA: American Institute for Cancer Research; SJF: NIH Grant 1-R01-CA131235-01A1 and NIH 1K24CA160653.
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Electronic supplementary material
41391_2018_45_MOESM2_ESM.tif
Effect of serum cholesterol reduction on liver and spleen size at 4 months of age in the PTEN-null transgenic mouse model
41391_2018_45_MOESM6_ESM.tif
Representative images of low and high Ki67 staining (A and B, respectively) and low and high TUNEL staining (C and D, respectively) at 4 months of age in the PTEN-null transgenic mouse model
41391_2018_45_MOESM7_ESM.tif
Effect of cholesterol reduction on proliferation and apoptosis in prostate tumor stroma at 4 months of age in the PTEN-null transgenic mouse model
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Allott, E.H., Masko, E.M., Freedland, A.R. et al. Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer. Prostate Cancer Prostatic Dis 21, 196–203 (2018). https://doi.org/10.1038/s41391-018-0045-x
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DOI: https://doi.org/10.1038/s41391-018-0045-x
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