Linking Cholesterol to Cancer: Circulating 27-Hydroxycholesterol and Breast Cancer Risk by Tumor Subtype and Expression of CYP27A1 and CYP7B1
Abstract
Rationale and Objectives of the Study: Recent experiments in breast cancer cells and mice have shown than a normal byproduct of the breakdown of cholesterol in our bodies might influence breast cancer risk. This byproduct is 27-hydroxycholesterol (27HC). Cholesterol is necessary for many processes in the body and is one of the building blocks for sex hormones such as estrogens and androgens. The cholesterol that does not eventually become a sex hormone can be broken down into 27HC. Experiments show that 27HC can communicate with breast cancer cells through the estrogen receptor (ER) in a similar fashion to estrogens. And, just as too much estrogen can increase risk of breast cancer, it appears that high levels of 27HC may increase risk as well. 27HC may act through damaging cells genetic code and increasing the rate at which cells multiply. Carefully conducted experiments in mice show that higher 27HC results in faster tumor growth, a faster increase in the number of breast cancer cells, and also that higher 27HC causes breast cancers to progress and spread more quickly beyond the breast to other parts of the body (i.e., metastasize). They also show that higher levels of the enzyme (CYP27A1) that converts cholesterol to 27HC results in faster tumor growth, as do low levels of the enzyme (CYP7B1) that is active in the breakdown of 27HC. In terms of cancer spread, activation of the liver X receptor (LXR) appears to be the primary pathway through which 27HC acts. These experimental studies provide compelling data supporting an important role for 27HC in breast cancer risk, but to date the vast majority of the data on 27HC and breast cancer are from experiments using breast cancer cells and mice. There are no prior studies evaluating pre-diagnostic blood samples and later risk of breast cancer in women. Therefore, our study proposes to extend these exciting experimental findings to a human population. Specifically, we propose to measure 27HC in blood samples collected at study recruitment in a group of women we have been following for health outcomes for up to two decades. Approximately 480 of these women developed breast cancer, and we have selected approximately 960 cancer-free women as a comparison group. This study will evaluate whether women with higher 27HC are at increased risk of breast cancer in our study population. We will also examine the tumor tissue of the majority of the cases included in our study to determine whether the 27HC concentrations in their blood is related to tumor expression of important factors in 27HC production, breakdown, and signaling. Our study objective is to provide the first epidemiologic data on pre-diagnostic 27HC and breast cancer risk and tumor characteristics. We will investigate the following hypotheses: (1) Higher circulating 27HC is associated with increased risk of breast cancer, and this association is strongest among tumors expressing the ER and in women with low circulating sex hormones (e.g., estrogens) or not taking hormones (e.g., postmenopausal hormones). (2) The positive association between 27HC and breast cancer is significantly stronger among women with tumors expressing the CYP27A1 enzyme and/or not expressing the CYP7B1 enzyme. (3) Higher circulating 27HC is positively associated with expression of the liver X receptor (LXR). This receptor potentially links 27HC to breast cancer spread. Ultimate Applicability: The goal of our research is to provide data to support primary prevention of breast cancer for high-risk women and to provide novel treatment targets for breast cancer patients. If 27HC is associated with breast cancer risk as we hypothesize, drugs that act as CYP27A1 blockers or CYP7B1 promoters would be important tools to reduce breast cancer risk and spread. The LXR would be an additional target to prevent 27HC-related metastases. This project addresses the following Breast Cancer Research Program Overarching Challenges: (1) Det
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510035
Entities
People
- S. Renee Turzanski Fortner
Organizations
- German Cancer Research Center
- United States Army