title: Altered microenvironment promotes progression of preinvasive breast cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence.
abstract: OBJECTIVE
  This study investigated the functional and clinical significance of integrin αvβ6 upregulation in myoepithelial cells of ductal carcinoma in situ (DCIS).
  
  
  METHODS
  Archival samples of DCIS and DCIS with associated invasion (n = 532) were analyzed for expression of αvβ6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, unique cohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without αvβ6 expression, were used to measure the effect of αvβ6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGFβ signaling was established using mink lung epithelial cell (MLEC) assay and antibody inhibition, and expression and activation of matrix metalloproteinase (MMP)-9 established by Real Time-PCR and zymography.
  
  
  RESULTS
  Expression of αvβ6 is significantly associated with progression to invasive cancer (P < 0.006) and with recurrence over a median follow-up of 114 months in a series of matched DCIS cases treated with local excision. We show that expression of αvβ6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of αvβ6-positive myoepithelial cells is dependent on TGFβ-driven upregulation of MMP9 and can be abrogated by inhibiting this pathway.
  
  
  CONCLUSIONS
  These findings indicate that altered myoepithelial cells in DCIS predict disease progression and recurrence and show that upregulation of αvβ6 on myoepithelial cells generates a tumor promoter function through TGFβ upregulation of MMP-9. These data suggest that expression of αvβ6 may be used to stratify patients with DCIS.
authors.affiliation: Authors' Affiliations: Barts Cancer Institute-a CR-UK Centre of Excellence, Centre for Tumour Biology, Queen Mary University of London, John Vane Science Centre; Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London,Cancer Research UK Clinical Centre, Somers Cancer Research Building, Experimental Pathology Group, Southampton General Hospital, Southampton; and Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich, Norfolk, United Kingdom.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Allen
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
authors.forename: Sarah
authors.initials: S
authors.lastname: Clark
authors.forename: Marwa M
authors.initials: MM
authors.lastname: Dawoud
authors.forename: Sabarinath
authors.initials: S
authors.lastname: Vallath
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Payne
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Gomm
authors.forename: Sally A
authors.initials: SA
authors.lastname: Dreger
authors.forename: Sarah
authors.initials: S
authors.lastname: Dickinson
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Pennington
authors.forename: Ivana
authors.initials: I
authors.lastname: Sestak
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.forename: John F
authors.initials: JF
authors.lastname: Marshall
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.forename: J Louise
authors.initials: JL
authors.lastname: Jones
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D002460:Cell Line; D045744:Cell Line, Tumor; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008907:Mink; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D020780:Matrix Metalloproteinase 9