title: Integrin α3β1 can function to promote spontaneous metastasis and lung colonization of invasive breast carcinoma.
abstract: Significant evidence implicates α3β1 integrin in promoting breast cancer tumorigenesis and metastasis-associated cell behaviors in vitro and in vivo. However, the extent to which α3β1 is actually required for breast cancer metastasis remains to be determined. We used RNA interference to silence α3 integrin expression by approximately 70% in 4T1 murine mammary carcinoma cells, a model of aggressive, metastatic breast cancer. Loss of α3 integrin reduced adhesion, spreading, and proliferation on laminin isoforms, and modestly reduced the growth of orthotopically implanted cells. However, spontaneous metastasis to lung was strikingly curtailed. Experimental lung colonization after tail vein injection revealed a similar loss of metastatic capacity for the α3-silenced (α3si) cells, suggesting that critical, α3-dependent events at the metastatic site could account for much of α3β1's contribution to metastasis in this model. Reexpressing α3 in the α3si cells reversed the loss of metastatic capacity, and silencing another target, the small GTPase RhoC, had no effect, supporting the specificity of the effect of silencing α3. Parental, α3si, and α3-rescued cells, all secreted abundant laminin α5 (LAMA5), an α3β1 integrin ligand, suggesting that loss of α3 integrin might disrupt an autocrine loop that could function to sustain metastatic growth. Analysis of human breast cancer cases revealed reduced survival in cases where α3 integrin and LAMA5 are both overexpressed.
  
  
  CONCLUSIONS
  α3 integrin or downstream effectors may be potential therapeutic targets in disseminated breast cancers, especially when laminin α5 or other α3 integrin ligands are also over-expressed.
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Gibson-Corley
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Herndon
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Gustafson-Wagner
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Teoh-Fitzgerald
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA, 52242 USA.|Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, 52242 USA.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Frederick E
authors.initials: FE
authors.lastname: Domann
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA, 52242 USA.|Department of Molecular Physiology & Biophysics, University of Iowa, Iowa City, IA, 52242 USA.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Henry
authors.affiliation: Department of Biology, University of Iowa, Iowa City, IA, 52242 USA.|Department of Molecular Physiology & Biophysics, University of Iowa, Iowa City, IA, 52242 USA.|Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242 USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stipp
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D006801:Humans; D039201:Integrin alpha3beta1 / Q000096:biosynthesis / Q000235:genetics*; D007797:Laminin / Q000096:biosynthesis / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D020033:Protein Isoforms; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D013534:Survival; D020741:rho GTP-Binding Proteins / Q000235:genetics; D000075024:rhoC GTP-Binding Protein
chemical_list: D039201:Integrin alpha3beta1; D007797:Laminin; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C097043:laminin alpha5; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein