title: Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer.
abstract: Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in breast cancer, is a well-established regulator of central glucose metabolism and aerobic glycolysis, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21(Cip1/WAF1) and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both in vitro and in vivo. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Lien
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Costas A
authors.identifier: 0000-0001-9309-6141
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Juvekar
authors.affiliation: Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
mesh_terms: D053898:Biosynthetic Pathways / Q000235:genetics; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000096:biosynthesis*; D006801:Humans; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019328:Buthionine Sulfoximine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione; D002945:Cisplatin