title: 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology.
abstract: Hypercholesterolemia is a risk factor for estrogen receptor (ER)-positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here, we show that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and liver X receptor (LXR) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1 and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Nelson
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Jasper
authors.forename: Sunghee
authors.initials: S
authors.lastname: Park
authors.forename: Sunil
authors.initials: S
authors.lastname: Suchindran
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Howe
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Carver
authors.forename: Ruchita V
authors.initials: RV
authors.lastname: Pillai
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sullivan
authors.forename: Varun
authors.initials: V
authors.lastname: Sondhi
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D053493:Cholestanetriol 26-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D006888:Hydroxycholesterols; C076996:27-hydroxycholesterol; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase