title: 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth.
abstract: To date, estrogen is the only known endogenous estrogen receptor (ER) ligand that promotes ER+ breast tumor growth. We report that the cholesterol metabolite 27-hydroxycholesterol (27HC) stimulates MCF-7 cell xenograft growth in mice. More importantly, in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to that in cancer-free controls, and tumor 27HC content is further elevated. Increased tumor 27HC is correlated with diminished expression of CYP7B1, the 27HC metabolizing enzyme, and reduced expression of CYP7B1 in tumors is associated with poorer patient survival. Moreover, 27HC is produced by MCF-7 cells, and it stimulates cell-autonomous, ER-dependent, and GDNF-RET-dependent cell proliferation. Thus, 27HC is a locally modulated, nonaromatized ER ligand that promotes ER+ breast tumor growth.
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Vascular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.forename: Tomonori
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Rosa
authors.initials: R
authors.lastname: Sirianni
authors.forename: Hao
authors.initials: H
authors.lastname: Tang
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: McDonald
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.forename: Bonne
authors.initials: B
authors.lastname: Thompson
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.forename: David M
authors.initials: DM
authors.lastname: Euhus
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D000072474:Cytochrome P450 Family 7; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D006888:Hydroxycholesterols; D011960:Receptors, Estrogen; C076996:27-hydroxycholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human