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Urinary Metalloproteinases: Noninvasive Biomarkers for Breast Cancer Risk Assessment

¹ Department of Surgery, Beth Israel Deaconess Medical Center and Mount Auburn Hospital; ² Vascular Biology Program and Department of Surgery, Children's Hospital of Boston; ³ Department of Radiation Oncology, Mount Auburn Hospital; ⁴ Department of Radiology, Brigham and Women's Hospital; ⁵ Department of Medical Oncology, Dana-Farber Harvard Cancer Institute; Departments of ⁶ Medical Oncology and ⁷ Nursing, Beth Israel Deaconess Medical Center; ⁸ Harvard Medical School, Boston, Massachusetts and ⁹ Institute of Molecular Pathology, University of Copenhagen, Copenhagen Denmark

Requests for reprints: Marsha A. Moses, Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Karp Family Research Building, 12.214, 300 Longwood Avenue, Boston, MA 02115-5737. Phone: 617-919-2207; Fax: 617-730-0231. E-mail: marsha.moses{at}childrens.harvard.edu

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. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1034–12)