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. 2018 Jun;21(2):196-203.
doi: 10.1038/s41391-018-0045-x. Epub 2018 May 23.

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

Emma H Allott  1 , Elizabeth M Masko  2 , Alexis R Freedland  3 , Everardo Macias  3 , Kristine Pelton  4 , Keith R Solomon  5   6 , Elahe A Mostaghel  7   8 , George V Thomas  9   10 , Salvatore V Pizzo  11 , Michael R Freeman  3 , Stephen J Freedland  12   13
Affiliations

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

Emma H Allott et al. Prostate Cancer Prostatic Dis. 2018 Jun.

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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Conflict of interest statement

Conflicts of interest: The authors have no conflicts of interest.

Figures

Figure 1
Figure 1
Caloric intake (A) and body weight (B) trajectories throughout the study duration in the PTEN-null transgenic mouse model of prostate cancer, median differences in serum cholesterol level between dietary groups at 4 months of age (C), and correlation between body weight at 4 months of age and serum cholesterol levels (D).
Figure 2
Figure 2
Effect of serum cholesterol reduction on prostate weight at 4 months of age in the PTEN-null transgenic mouse model
Figure 3
Figure 3
Effect of cholesterol reduction on proliferation and apoptosis in prostate tumor epithelium at 4 months of age in the PTEN-null transgenic mouse model
See this image and copyright information in PMC

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