title: Urinary metalloproteinases: noninvasive biomarkers for breast cancer risk assessment.
abstract: Matrix metalloproteinases (MMP) and a disintegrin and metalloprotease 12 (ADAM 12) can be detected in the urine of breast cancer patients and provide independent prediction of disease status. To evaluate the potential of urinary metalloproteinases as biomarkers to predict breast cancer risk status, urine samples from women with known risk marker lesions, atypical hyperplasia and lobular carcinoma in situ (LCIS), were analyzed. Urine samples were obtained from 148 women: 44 women with atypical hyperplasia, 24 women with LCIS, and 80 healthy controls. MMP analysis was done using gelatin zymography and ADAM 12 analysis was done via immunoblotting with monospecific antibodies and subsequent densitometric measurement. Positive urinary MMP-9 levels indicated a 5-fold risk of atypical hyperplasia and >13-fold risk of LCIS compared with normal controls. Urinary ADAM 12 levels were significantly elevated in women with atypical hyperplasia and LCIS from normal controls, with receiver operating characteristic curve analysis showing an area under the curve of 0.914 and 0.950, respectively. To assess clinical applicability, a predictive index was developed using ADAM 12 in conjunction with Gail risk scores for women with atypia. Scores above 2.8 on this ADAM 12-Gail risk prediction index score are predictive of atypical hyperplasia (sensitivity, 0.976; specificity, 0.977). Our data suggest that the noninvasive detection and analysis of urinary ADAM 12 and MMP-9 provide important clinical information for use as biomarkers in the identification of women at increased risk of developing breast cancer.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center and Mount Auburn Hospital, Boston, MA, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Pories
authors.forename: David
authors.initials: D
authors.lastname: Zurakowski
authors.forename: Roopali
authors.initials: R
authors.lastname: Roy
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Lamb
authors.forename: Sughra
authors.initials: S
authors.lastname: Raza
authors.forename: Alexis
authors.initials: A
authors.lastname: Exarhopoulos
authors.forename: Rochelle G
authors.initials: RG
authors.lastname: Scheib
authors.forename: Susan
authors.initials: S
authors.lastname: Schumer
authors.forename: Corrine
authors.initials: C
authors.lastname: Lenahan
authors.forename: Virginia
authors.initials: V
authors.lastname: Borges
authors.forename: Gwendolyn W
authors.initials: GW
authors.lastname: Louis
authors.forename: Ankur
authors.initials: A
authors.lastname: Anand
authors.forename: Nina
authors.initials: N
authors.lastname: Isakovich
authors.forename: Judi
authors.initials: J
authors.lastname: Hirshfield-Bartek
authors.forename: Ulla
authors.initials: U
authors.lastname: Wewer
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Lotz
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Moses
mesh_terms: D051722:ADAM Proteins / Q000652:urine; D000072199:ADAM12 Protein; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000652:urine*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000652:urine*; D002278:Carcinoma in Situ / Q000201:enzymology / Q000652:urine; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D016015:Logistic Models; D020780:Matrix Metalloproteinase 9 / Q000652:urine; D008565:Membrane Proteins / Q000652:urine; D045726:Metalloproteases / Q000652:urine*; D008875:Middle Aged; D011230:Precancerous Conditions / Q000201:enzymology / Q000652:urine; D018570:Risk Assessment
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D045726:Metalloproteases; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human; D020780:Matrix Metalloproteinase 9