title: γKlotho is a novel marker and cell survival factor in a subset of triple negative breast cancers.
abstract: Over the last decade, breast cancer mortality has declined. However, triple negative breast cancer (TNBC) remains a challenging problem mostly due to early recurrence and lack of molecularly driven treatments. There is a critical need to identify subgroups of TNBC with common molecular features that can be therapeutically targeted. Here we show that in contrast to Klotho and βKlotho, the third member of the Klotho protein family, γKlotho, is overexpressed in more than 60% of TNBCs and correlates with poorer disease progression. Furthermore, we find that γKlotho is expressed in a subset of TNBC cell lines promoting cell growth. Importantly, we demonstrate that in these cells γKlotho is necessary for cell survival and that its depletion leads to constitutive ERK activation, cell cycle arrest and apoptosis. Interestingly, we observe increased oxidative stress in γKlotho-depleted cells suggesting that γKlotho enables cancer cells to cope with an oxidative environment and that cells become dependent on its expression to maintain this survival advantage. These findings indicate that γKlotho might be a potential marker for patients that would benefit from treatments that alter oxidative stress and constitutes a novel drug target for a subset of TN breast cancers.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.|Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Nuša
authors.initials: N
authors.lastname: Trošt
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Peña-Llopis
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sajjan
authors.initials: S
authors.lastname: Koirala
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Jurij
authors.initials: J
authors.lastname: Stojan
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Patrick Ryan
authors.initials: PR
authors.lastname: Potts
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|klementina.fontacer@stjude.org
authors.forename: Klementina
authors.initials: K
authors.lastname: Fon Tacer
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Elisabeth D
authors.initials: ED
authors.lastname: Martinez
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000145:classification / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: FGF; Klotho; TNBC; cancer therapy; oxidative stress