title: A putative role for psoriasin in breast tumor progression.
abstract: Psoriasin (S100A7) was identifi;ed as a gene highly expressed in psoriatic keratinocytes and highly and more frequently expressed in ductal carcinoma in situ (DCIS) than in invasive breast carcinomas (IBC), suggesting a potential role in tumor progression. Psoriasin expression is associated with poor prognostic factors in both DCIS and IBC. Several putative functions have been proposed for psoriasin in various disease types, but none of these can fully explain its involvement in breast tumor progression. Here, we show that down-regulation of endogenous psoriasin expression via stable short hairpin RNAs in a human IBC cell line (MDA-MB-468) increases cell migration and invasion without influencing cell proliferation and survival in vitro but inhibits tumor growth in vivo. These seemingly paradoxical results are potentially explained by the dramatic up-regulation and down-regulation of matrix metalloproteinase-13 and vascular endothelial growth factor (VEGF), respectively, observed in cells with decreased psoriasin levels compared with controls. Correlating with this, high psoriasin expression in human IBC is associated with increased angiogenesis and worse clinical outcome, and psoriasin mRNA levels are coordinately regulated with VEGF and other genes related to hypoxia and mitochondrial reactive oxygen species (ROS). Based on these results, we propose that psoriasin may play a role in breast tumor progression by promoting angiogenesis and enhancing the selection for cells that overcome its anti-invasive function. This hypothesis may explain why psoriasin expression is highest in high-grade and/or estrogen receptor-negative tumors, as these are associated with increased hypoxia and ROS, a setting in which the angiogenic effects of psoriasin are most important.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Krop
authors.forename: Annette
authors.initials: A
authors.lastname: März
authors.forename: Hanna
authors.initials: H
authors.lastname: Carlsson
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.forename: Noga
authors.initials: N
authors.lastname: Bloushtain-Qimron
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gelman
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sabel
authors.forename: Stuart
authors.initials: S
authors.lastname: Schnitt
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Celina G
authors.initials: CG
authors.lastname: Kleer
authors.forename: Charlotta
authors.initials: C
authors.lastname: Enerbäck
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000502:physiology; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D017364:Collagenases / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D042461:Vascular Endothelial Growth Factor A; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse