The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer

D. P. Mcdonnell, C. Y. Chang, Erik Nelson

Research output: Contribution to journalArticle

Abstract

Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.

Original languageEnglish (US)
Pages (from-to)60-65
Number of pages6
JournalClimacteric
Volume17
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

Fingerprint

Estrogen Receptors
Cholesterol
Breast Neoplasms
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Obesity
Incidence
Neoplasms
Pharmacology
Diet Therapy
High Fat Diet
Hypercholesterolemia
Life Style
Cause of Death
Estrogens
Survival Rate
Animal Models
Neoplasm Metastasis
Recurrence
Growth
27-hydroxycholesterol

Keywords

  • 27-hydroxycholesterol
  • Breast Cancer
  • Cyp27a1
  • Serm
  • Statins

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Medicine(all)

Cite this

The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer. / Mcdonnell, D. P.; Chang, C. Y.; Nelson, Erik.

In: Climacteric, Vol. 17, 01.12.2014, p. 60-65.

Research output: Contribution to journalArticle

@article{e37025e02b8f4bec83c7e8962ecf5634,
title = "The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer",
abstract = "Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.",
keywords = "27-hydroxycholesterol, Breast Cancer, Cyp27a1, Serm, Statins",
author = "Mcdonnell, {D. P.} and Chang, {C. Y.} and Erik Nelson",
year = "2014",
month = "12",
day = "1",
doi = "10.3109/13697137.2014.966949",
language = "English (US)",
volume = "17",
pages = "60--65",
journal = "Climacteric",
issn = "1369-7137",
publisher = "Informa Healthcare",

}

TY - JOUR

T1 - The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer

AU - Mcdonnell, D. P.

AU - Chang, C. Y.

AU - Nelson, Erik

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.

AB - Despite increased survivorship among patients, breast cancer remains the most common cancer among women and is the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. It is of significance, therefore, that several studies positively correlate obesity to the development of breast cancer. Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients taking statins demonstrate a lower breast cancer incidence and decreased recurrence. The recent observation that 27-hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our recent demonstration that it exerts partial agonist activity on both the estrogen and liver X receptors, suggested a potential mechanistic link between hyper-cholesterolemia and breast cancer incidence. Using genetic and pharmacological approaches, we have recently shown that elevation of circulating 27HC significantly increases tumor growth and metastasis in murine models of breast cancer. Further, we have demonstrated in appropriate animal models that the impact of high-fat diet on tumor pathogenesis can be mitigated by statins or by small molecule inhibitors of CYP27A1. These findings suggest that pharmacological or dietary modifications that lower total cholesterol, and by inference 27HC, are likely to reduce the impact of obesity/metabolic syndrome on breast cancer incidence.

KW - 27-hydroxycholesterol

KW - Breast Cancer

KW - Cyp27a1

KW - Serm

KW - Statins

UR - http://www.scopus.com/inward/record.url?scp=84911367757&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911367757&partnerID=8YFLogxK

U2 - 10.3109/13697137.2014.966949

DO - 10.3109/13697137.2014.966949

M3 - Article

C2 - 25320023

AN - SCOPUS:84911367757

VL - 17

SP - 60

EP - 65

JO - Climacteric

JF - Climacteric

SN - 1369-7137

ER -