Despite increased survivorship among patients, breast cancer remains the second leading cause of cancer death in women. The magnitude of this problem provides a strong impetus for studies that may lead to the development of new chemopreventative strategies and/or lifestyle changes that reduce cancer incidence. In this regard, several studies positively correlate obesity to the development of breast cancer. Current evidence and proposed mechanisms for this observation strongly implicate the involvement of the estrogen receptor (ER). Importantly, obesity is also highly associated with elevated cholesterol, and cholesterol itself is a risk factor for breast cancer. Furthermore, patients takin lipophilic inhibitors of HMG-CoA reductase (statins) demonstrate a decreased risk for breast cancer incidence and recurrence. The recent observation that 27- hydroxycholesterol (27HC) is produced in a stoichiometric manner from cholesterol, together with our data demonstrating that it exerts partial agonist activity on both the ERs and liver X receptors (LXRs), suggests a potential, heretofore unrecognized, mechanistic link between hypercholesterolemia and breast cancer incidence. Several key pieces of evidence form the foundation of the proposed project: (1) obesity, metabolic syndrome and high serum cholesterol are all associated with increased breast cancer incidence, (2) enrichment of tumor-associated macrophages, the primary producers of 27HC, in the tumor microenvironment is associated with a poor prognosis, and (3) elevation of 27HC levels in a murine model of spontaneous mammary cancer increases tumor growth and metastasis in vivo. Building on these findings we hypothesize that 27HC, through its actions on ER and LXR, is an important mechanistic link between obesity, hypercholesterolemia and increased incidence of breast cancer. My long-term goal is to develop an independent research program focused on defining how manipulation of cholesterol biology, pathologically or pharmacologically, impacts the initiation and progression of breast cancer. With the help of the highly qualified mentors and advisory committee members that I have selected, along with the exceptional research environment at Duke University School of Medicine, I am very well situated to address the important questions being asked in this proposal. At the conclusion of this project I expect to have (1) established mechanistic links between obesity, cholesterol and increased susceptibility, growth and metastasis of breast cancer, (2) evaluated the utility of targeting cholesterol and 27HC production, and relevant downstream signaling pathways in the treatment and prevention of breast cancer, and (3) defined the mechanisms by which 27HC increases metastasis. It is anticipated that this line of investigation will lead to the near-term development of new strategies to treat and prevent breast cancer. Furthermore, the results will likely provide additional support and rationale for the exploration of potential chemopreventative benefits of lower cholesterol diets and/or pharmacological inhibitors of HMG-CoA reductase or CYP27A1.
The elevated breast cancer risk associated with obesity in women has been attributed to increases in circulating insulin and insulin-like growth factors, increased aromatase expression in adipose tissue, and the influence of obesity-related inflammatory cytokines on the tumor and its microenvironment. However, there are additional studies that suggest that hypercholesterolemia, an obesity comorbidity, may also be linked to increased breast cancer risk. Furthermore, statin use has been shown to be associated with a significant reduction in breast cancer incidence and recurrence. Together these findings put in context our observation that cholesterol, subsequent to its conversion to its primary metabolite 27-hydroxycholesterol (27HC), increases tumor growth, reduces tumor latency and increases in metastasis in animal models of luminal breast cancer. In this proposal we will define the mechanisms by which 27HC impacts tumor pathogenesis and evaluate the potential impact of interfering with the synthesis and or activity of this oxysterol as a means to reduce breast cancer risk. Given that that 65%-80% of women 55-74 years of age are hypercholesterolemic, as defined by total cholesterol levels of greater than 5.18mM, the potential impact of these studies is immense. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the Critique section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The Resume and Summary of Discussion section above summarizes the final opinions of the committee.
|McDonnell, D P; Chang, C-Y; Nelson, E R (2014) The estrogen receptor as a mediator of the pathological actions of cholesterol in breast cancer. Climacteric 17 Suppl 2:60-5|
|Nelson, Erik R; Chang, Ching-yi; McDonnell, Donald P (2014) Cholesterol and breast cancer pathophysiology. Trends Endocrinol Metab 25:649-55|
|McDonnell, Donald P; Park, Sunghee; Goulet, Matthew T et al. (2014) Obesity, cholesterol metabolism, and breast cancer pathogenesis. Cancer Res 74:4976-82|
|Nelson, Erik R; Wardell, Suzanne E; Jasper, Jeff S et al. (2013) 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology. Science 342:1094-8|