title: Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression.
abstract: BACKGROUND
  A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease.
  
  
  METHODS
  The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided.
  
  
  RESULTS
  Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR = 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties.
  
  
  CONCLUSIONS
  These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of beneﬁt.
authors.affiliation: Department of Pathology, University of Texas Southwestern, Dallas, TX 75390. knudsen.esk@gmail.com
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Pajak
authors.forename: Maria
authors.initials: M
authors.lastname: Qeenan
authors.forename: A Kathleen
authors.initials: AK
authors.lastname: McClendon
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Armon
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Schwartz
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000378:metabolism*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016017:Odds Ratio; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D019572:Retinal Neoplasms; D012175:Retinoblastoma / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human