Obesity increases the risk of post-menopausal estrogen receptor (ER)-positive breast cancer by over 50%, a significant observation given that 40% of the US population are clinically obese and that obesity is rising most rapidly in women over 60 years of age. Some of this risk can be attributed to increased estrogen production in adipose tissue and to obesity-associated increases in inflammatory cytokines, IGF-1, and circulating insulin. Recently, however, altered cholesterol metabolism, a comorbidity of obesity, has emerged as an additional independent risk factor for breast cancer in post-menopausal women. It is significant, therefore, that we demonstrated that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol, functions as an estrogen in cellular and animal models of ER-positive breast cancer. Notably, the impact of hypercholesterolemia on tumor pathology was reduced in mice in which CYP27A1, the enzyme responsible for converting cholesterol to 27HC, was ablated. The clinical relevance of these findings was confirmed in our studies demonstrating that increased expression of CYP27A1 within tumors was associated with a higher grade. This was reinforced by the findings of another group indicating that 27HC levels were significantly elevated in breast tumor tissue. We also demonstrated in animal models that elevation of 27HC dramatically increased tumor metastasis through its actions on the nuclear receptor LXR. Together, these findings establish 27HC as an important biochemical link between hypercholesterolemia and breast cancer and implicate ER and LXR as the primary mediators of these activities. Building on these findings, we hypothesize that the oxysterol, 27HC, is an endocrine/paracrine modulator of processes that impact breast tumor growth and metastasis. It is further proposed that LXR and ER are the primary mediators of the pathological actions of 27HC and that these activities result from a dysregulation of pathways upon which these receptors converge. To explore this hypothesis we will (a) define the temporal and spatial relationship between 27HC production and the development and progression of breast cancer, (b) explore therapeutic strategies to mitigate the impact of hypercholesterolemia on cancer pathology, and (c) define the pathways of pathological importance upon which ER and LXR converge and how this influences the pharmacology of 27HC. Together, these integrated experiments probe fundamental aspects of 27HC endocrinology/pharmacology that will enable a definition of the roles of ER/LXR crosstalk in breast cancer pathology. The heavy focus on development of therapeutics reflects the expectation that these studies will yield the data required to inform near term clinical trials of agents to mitigate the impact of hypercholesterolemia on breast cancer.

Public Health Relevance

Obesity increases the risk of post-menopausal estrogen receptor (ER) positive breast cancer by over 50%, a significant observation given that 40% of the US population are clinically obese and that obesity is rising most rapidly in women over 60 years of age. Recently, altered cholesterol metabolism, a comorbidity of obesity, has emerged as an additional independent risk factor for breast cancer in post-menopausal women. 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 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK048807-24
Application #
9412452
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Silva, Corinne M
Project Start
1994-12-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
24
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Baek, Amy E; Yu, Yen-Rei A; He, Sisi et al. (2017) The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nat Commun 8:864
Alfaqih, Mahmoud A; Nelson, Erik R; Liu, Wen et al. (2017) CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer. Cancer Res 77:1662-1673
Anderson, Grace R; Wardell, Suzanne E; Cakir, Merve et al. (2016) PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation. Sci Transl Med 8:369ra175
Wardell, Suzanne E; Ellis, Matthew J; Alley, Holly M et al. (2015) Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer. Clin Cancer Res 21:5121-5130
McDonnell, Donald P; Wardell, Suzanne E; Norris, John D (2015) Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer. J Med Chem 58:4883-7
Choudhary, Mayur; Kazmin, Dmitri; Hu, Peng et al. (2015) Aryl hydrocarbon receptor knock-out exacerbates choroidal neovascularization via multiple pathogenic pathways. J Pathol 235:101-12
Wardell, Suzanne E; Nelson, Erik R; Chao, Christina A et al. (2015) Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocr Relat Cancer 22:713-24
Martz, Colin A; Ottina, Kathleen A; Singleton, Katherine R et al. (2014) Systematic identification of signaling pathways with potential to confer anticancer drug resistance. Sci Signal 7:ra121
Scholtz, Elizabeth L; Krishnan, Shweta; Ball, Barry A et al. (2014) Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5?-dihydroprogesterone. Proc Natl Acad Sci U S A 111:3365-70
Nelson, Erik R; Chang, Ching-yi; McDonnell, Donald P (2014) Cholesterol and breast cancer pathophysiology. Trends Endocrinol Metab 25:649-55

Showing the most recent 10 out of 70 publications