Nodular thyroid disease is common and its pathogenesis remains poorly understood. Previously, we showed that thyroid-targeted overexpression of the proto-oncogene PTTG-Binding Factor (PBF) induced striking thyroid gland enlargement in transgenic mice (PBF-Tg)1. We have now investigated whether dietary factors influence goitrogenesis and the development of hyperplastic lesions in PBF-Tg mice. The mean weight of thyroids (5.8±0.9 mg; n=70) from 7 week old PBF-Tg mice fed on a phytoestrogen-reduced Teklad diet was significantly greater (P<0.0001) than PBF-Tg mice fed their normal RM-3 diet (3.2±0.7 mg; n=98). In contrast, there was no significant difference in the mean thyroid weight of age-matched wild-type mice fed either the Teklad (2.15±0.5 mg; n=60) or RM-3 diet (1.8±0.4 mg; n=68). This increase in thyroid weight was not related to differences in body weight (25.0±1.9g v 24.7±2.4g; P=0.5) or thyroid function, as measured by serum analysis of T3 (172.7±25.9 versus 154.1±46.9 ng/dl, P=0.45), and T4 levels (2.7±0.7 versus 3.2±1.2 μg/dl, P=0.45), between PBF-Tg mice fed either the Teklad or RM-3 diet, respectively. Analysis of mRNAs encoding growth factor receptors known to induce thyroid cell proliferation showed a significant increase in expression of PDGFR (1.6±0.3-fold, P=0.0001), FGFR2 (1.5±0.2-fold, P=0.0001), KDR (1.4±0.2-fold, P=0.003), and ERBB2 (1.4±0.2-fold, P=0.0003) in thyroids from PBF-Tg mice fed the Teklad diet compared to those on the RM-3 diet. Furthermore, focal hyperplastic lesions were detected by histological examination in thyroids from PBF-Tg mice at a younger age when fed the Teklad diet (~8 months) versus the RM-3 diet (≥12 months). Positive immunostaining with antibodies targeted to Rad51, Ung1, Trex1, and Xrcc3 also suggested extensive DNA damage within hyperplastic lesions. These results demonstrate that dietary factors can modulate the induction of goitrogenesis and hyperplasia by PBF in vivo, which has implications for understanding the relative contributions of dietary and genetic factors on the rate of nodular transformation and tumorigenesis. 1Read ML et al. (2011) Cancer Research 71(19): 6153–6164.