Nilesh W. Gaikwad¹, Li Yang¹, Sandhya Pruthi², James N. Ingle³, Nicole Sandhu², Eleanor G. Rogan^1,4 and Ercole L. Cavalieri¹

¹Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805. ²Breast Diagnostic Clinic, Internal Medicine, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. ³Department of Medical Oncology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. ⁴Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, 985110 Nebraska Medical Center, Omaha, NE 68198-5110.

Abstract

Endogenous estrogens can be bio-activated to endogenous carcinogens via formation of estrogen quinones. Estrogen-3,4-quinones react with DNA to form mutagenic depurinating estrogen-DNA adducts. The carcinogenicity of endogenous estrogens is related to unbalanced estrogen metabolism leading to excess estrogen quinones and formation of depurinating DNA adducts. The present studies were initiated to confirm that relatively high levels of depurinating estrogen- DNA adducts are present in women at high risk for breast cancer or diagnosed with the disease. These adducts may be biomarkers for early detection of breast cancer risk. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry to analyze urine samples from 40 healthy control women, 40 high-risk women and 40 women with newly diagnosed breast cancer. Estrogen metabolism was shifted from protective methoxylation and conjugation pathways in healthy control women towards activating pathways leading to formation of depurinating DNA adducts in women at high risk or with breast cancer. These results support the hypothesis that breast cancer is initiated by mutations derived from depurination of estrogen-DNA adducts. Therefore, relative levels of depurinating estrogen-DNA adducts could become biomarkers for early detection of breast cancer risk and aid in determining preventive strategies.