title: PPARγ maintains ERBB2-positive breast cancer stem cells.
abstract: Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers and is associated with aggressive disease and poor outcomes. Our recent findings have shown that NR1D1 and the peroxisome proliferator-activated receptor-γ (PPARγ)-binding protein (PBP) act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. NR1D1 and PBP are functionally related to PPARγ, a well-established positive regulator of adipogenesis and lipid storage. Here, we report that inhibition of the PPARγ pathway reduces the aldehyde dehydrogenase (ALDH)-positive population in ERBB2-positive breast cancer cells. Results from in vitro tumorsphere formation assays demonstrate that the PPARγ antagonists GW9662 and T0070907 decrease tumorsphere formation in ERBB2-positive cells, but not other breast cells. We show that the mechanism by which GW9662 treatment causes a reduction in ALDH-positive population cells is partially due to ROS, as it can be rescued by treatment with N-acetyl-cysteine. Furthermore, global gene expression analyses show that GW9662 treatment suppresses the expression of several lipogenic genes, including ACLY, MIG12, FASN and NR1D1, and the stem-cell related genes KLF4 and ALDH in BT474 cells. Antagonist treatment also decreases the level of acetylation in histone 3 and histone 4 in BT474 cells, compared with MCF7 cells. In vivo, GW9662 pre-treatment inhibits the tumor-seeding ability of BT474 cells. Together, these results show that the PPARγ pathway is critical for the cancer stem cell properties of ERBB2-positive breast cancer cells.
authors.affiliation: Department of Biomedical Sciences, Cancer Research Center, University at Albany, State University of New York, Rensselaer, NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: J
authors.initials: J
authors.lastname: Wong
authors.forename: D S
authors.initials: DS
authors.lastname: Conklin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D061986:MCF-7 Cells; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D000111:Acetylcysteine; D000444:Aldehyde Dehydrogenase; D000813:Anilides; D001549:Benzamides; D000090062:Kruppel-Like Factor 4; D056913:Mediator Complex Subunit 1; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047495:PPAR gamma; D011725:Pyridines; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C457499:2-chloro-5-nitrobenzanilide; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C064353:NR1D1 protein, human; C458508:T 0070907; C508053:ERBB2 protein, human