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

Emma H. Allott, Elizabeth M. Masko, Alexis R. Freedland, Everardo Macias, Kristine Pelton, Keith R. Solomon, Elahe A. Mostaghel, George Thomas, Salvatore V. Pizzo, Michael R. Freeman, Stephen J. Freedland

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalProstate Cancer and Prostatic Diseases
DOIs
StateAccepted/In press - May 23 2018

Fingerprint

Transgenic Mice
Prostatic Neoplasms
Cholesterol
Growth
Serum
Neoplasms
Androgens
Prostate
Testosterone
Adenocarcinoma
Anticholesteremic Agents
Apoptosis
Dehydroepiandrosterone
Androstenedione
In Situ Nick-End Labeling
High Fat Diet
Stromal Cells
Weaning
Growth and Development
Mass Spectrometry

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

Cite this

Allott, E. H., Masko, E. M., Freedland, A. R., Macias, E., Pelton, K., Solomon, K. R., ... Freedland, S. J. (Accepted/In press). Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer. Prostate Cancer and Prostatic Diseases, 1-8. https://doi.org/10.1038/s41391-018-0045-x

Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer. / Allott, Emma H.; Masko, Elizabeth M.; Freedland, Alexis R.; Macias, Everardo; Pelton, Kristine; Solomon, Keith R.; Mostaghel, Elahe A.; Thomas, George; Pizzo, Salvatore V.; Freeman, Michael R.; Freedland, Stephen J.

In: Prostate Cancer and Prostatic Diseases, 23.05.2018, p. 1-8.

Research output: Contribution to journalArticle

Allott, EH, Masko, EM, Freedland, AR, Macias, E, Pelton, K, Solomon, KR, Mostaghel, EA, Thomas, G, Pizzo, SV, Freeman, MR & Freedland, SJ 2018, 'Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer', Prostate Cancer and Prostatic Diseases, pp. 1-8. https://doi.org/10.1038/s41391-018-0045-x
Allott, Emma H. ; Masko, Elizabeth M. ; Freedland, Alexis R. ; Macias, Everardo ; Pelton, Kristine ; Solomon, Keith R. ; Mostaghel, Elahe A. ; Thomas, George ; Pizzo, Salvatore V. ; Freeman, Michael R. ; Freedland, Stephen J. / Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer. In: Prostate Cancer and Prostatic Diseases. 2018 ; pp. 1-8.
@article{8ba0ce1d10e748619573f291638d05c8,
title = "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.",
author = "Allott, {Emma H.} and Masko, {Elizabeth M.} and Freedland, {Alexis R.} and Everardo Macias and Kristine Pelton and Solomon, {Keith R.} and Mostaghel, {Elahe A.} and George Thomas and Pizzo, {Salvatore V.} and Freeman, {Michael R.} and Freedland, {Stephen J.}",
year = "2018",
month = "5",
day = "23",
doi = "10.1038/s41391-018-0045-x",
language = "English (US)",
pages = "1--8",
journal = "Prostate Cancer and Prostatic Diseases",
issn = "1365-7852",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer

AU - Allott, Emma H.

AU - Masko, Elizabeth M.

AU - Freedland, Alexis R.

AU - Macias, Everardo

AU - Pelton, Kristine

AU - Solomon, Keith R.

AU - Mostaghel, Elahe A.

AU - Thomas, George

AU - Pizzo, Salvatore V.

AU - Freeman, Michael R.

AU - Freedland, Stephen J.

PY - 2018/5/23

Y1 - 2018/5/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85047275143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047275143&partnerID=8YFLogxK

U2 - 10.1038/s41391-018-0045-x

DO - 10.1038/s41391-018-0045-x

M3 - Article

C2 - 29795142

AN - SCOPUS:85047275143

SP - 1

EP - 8

JO - Prostate Cancer and Prostatic Diseases

JF - Prostate Cancer and Prostatic Diseases

SN - 1365-7852

ER -