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

Prostate Cancer and Prostatic Diseases volume 21, pages 196–203 (2018)Cite this article

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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

Funding

EHA: American Institute for Cancer Research; SJF: NIH Grant 1-R01-CA131235-01A1 and NIH 1K24CA160653.

Author information

Author notes

  1. Keith R. Solomon

    Present address: Applied Photophysics, Beverly, MA, USA

Authors and Affiliations

  1. Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Emma H. Allott

  2. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    Elizabeth M. Masko

  3. Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Alexis R. Freedland, Everardo Macias, Michael R. Freeman & Stephen J. Freedland

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Kristine Pelton

  5. The Urological Diseases Research Center, Boston Children’s Hospital, Boston, MA, USA

    Keith R. Solomon

  6. Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA

    Elahe A. Mostaghel

  7. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Elahe A. Mostaghel

  8. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

    George V. Thomas

  9. Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA

    George V. Thomas

  10. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    Salvatore V. Pizzo

  11. Division of Urology, Veterans Affairs Medical Center, Durham, NC, USA

    Stephen J. Freedland

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Corresponding author

Correspondence to Stephen J. Freedland.

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The authors declare that they have no conflict of interest.

Electronic supplementary material

Formulation of diets used in the current study

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

Effect of serum cholesterol reduction on liver function at 4 months of age in the PTEN-null transgenic mouse model

Definiens Tissue Studio algorithm to separate epithelium from stroma

Quantification of tumor epithelial staining using Definiens Tissue Studio

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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