In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I- symporter (NIS), whereas in the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2 of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total tissue iodine levels of 80.9 +/- 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher than those in 19 breast cancers taken from either the tumor (18.2 +/- 4.6 ng I/mg) or morphologically normal tissue taken from within the tumor-bearing breast (31.8 +/- 4.9 ng I/mg; P < 0.05 in each case). Inhibition of 125I uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49 (16.3%) benign breast disease, and 27 of 86 (31.4%) Graves' patients, but in only 1 of 33 (3.0%) age-matched female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly associated with thyroid peroxidase antibody positivity (P < 0.05) in sera from breast cancer patients, but not in those with benign breast disease, once again suggesting an association between thyroid autoimmunity and breast carcinoma.