title: Loss of BRCA1 in the Cells of Origin of Ovarian Cancer Induces Glycolysis: A Window of Opportunity for Ovarian Cancer Chemoprevention.
abstract: Mutations in the breast cancer susceptibility gene 1 (BRCA1) are associated with an increased risk of developing epithelial ovarian cancer. However, beyond the role of BRCA1 in DNA repair, little is known about other mechanisms by which BRCA1 impairment promotes carcinogenesis. Given that altered metabolism is now recognized as important in the initiation and progression of cancer, we asked whether the loss of BRCA1 changes metabolism in the cells of origin of ovarian cancer. The findings show that silencingBRCA1in ovarian surface epithelial and fallopian tube cells increased glycolysis. Furthermore, when these cells were transfected with plasmids carrying deleteriousBRCA1mutations (5382insC or the P1749R), there was an increase in hexokinase-2 (HK2), a key glycolytic enzyme. This effect was mediated by MYC and the STAT3. To target the metabolic phenotype induced by loss of BRCA1, a drug-repurposing approach was used and aspirin was identified as an agent that counteracted the increase in HK2 and the increase in glycolysis induced by BRCA1 impairment. Evidence from this study indicates that the tumor suppressor functions of BRCA1 extend beyond DNA repair to include metabolic endpoints and identifies aspirin as an ovarian cancer chemopreventive agent capable of reversing the metabolic derangements caused by loss of BRCA1.Cancer Prev Res; 10(4); 255-66. ©2017 AACR.
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Chiyoda
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hart
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Eckert
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: McGregor
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Ricardo R
authors.initials: RR
authors.lastname: Lastra
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: S Diane
authors.initials: SD
authors.lastname: Yamada
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, Illinois. iromero@babies.bsd.uchicago.edu.
authors.forename: Iris L
authors.initials: IL
authors.lastname: Romero
mesh_terms: D001241:Aspirin / Q000494:pharmacology; D019313:BRCA1 Protein / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018890:Chemoprevention / Q000379:methods; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005187:Fallopian Tubes / Q000378:metabolism; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D001241:Aspirin