Phytoestrogens influence the ability of the proto-oncogene PBF to promote goitrogenesis and hyperplasia

Martin Read, Vicki Smith, Gavin Ryan, Robert Seed, Neil Sharma, Gregory Lewy, Perkin Kwan, Jim Fong, Adrian Warfield, Wendy Leadbeater, John C. Watkinson, Jayne Franklyn, Kristien Boelaert, Christopher McCabe

Research output: Contribution to journalAbstractpeer-review

Abstract

A role for dietary phytoestrogens in preventing thyroid disease remains controversial. Previously, we showed that thyroid-targeted
overexpression of the proto-oncogene PTTG-binding factor (PBF) induced striking thyroid gland enlargement in transgenic mice (PBFTg)1
.
We have now investigated whether PBF-Tg mice fed on diets with
different amounts of phytoestrogens affect goitrogenesis and the development of hyperplastic lesions.
PBF-Tg mice fed on a low-phytoestrogen (PE) diet showed an
approximate doubling of thyroid weight (mean = 5.9 – 0.9 mg; n = 75)
at 6 weeks of age compared to PBF-Tg mice fed a high-PE diet
(3.3 – 0.8 mg; n = 98; p < 0.0001). In contrast, the thyroid weight of wildtype (WT) mice increased only marginally when fed the low-PE diet
(mean = 2.17 – 0.5 mg; n = 60) compared to the high-PE 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 = 0.3) or thyroid
function, as measured by serum analysis of T3 (172.7 – 25.9 versus
154.1 – 46.9 ng/dL, p = 0.5), and T4 levels (2.7 – 0.7 versus 3.2 – 1.2 lg/
dL, p = 0.5), between PBF-Tg mice fed either the low- or high-PE diet,
respectively. Analysis of mRNA showed a significant increase in cyclin D1 expression (1.6 – 0.2-fold, p = 0.008), as well as mRNAs encoding for growth factor receptors known to induce thyroid cell
proliferation, such as PDGFR (1.6 – 0.3-fold, p = 0.0001), FGFR2
(1.5 – 0.2-fold, p = 0.0001), and KDR (1.4 – 0.2-fold, p = 0.003), in thyroids from PBF-Tg mice fed the low-PE diet compared to those on the
high-PE diet. Furthermore, histological examination detected a
greater frequency of focal hyperplastic lesions in thyroids from 12-
month-old PBF-Tg mice fed the low-PE diet (83% of mice; n = 10/12)
versus the high PE diet (8.3% of mice; n = 1/12; p < 0.0001). No hyperplastic lesions were detected in thyroids from age-matched WT
mice (n = 0/12). Positive immunostaining with antibodies targeted to
Rad6, Ung1, and Trex1 also indicated extensive DNA damage within
hyperplastic lesions.
These results suggest that phytoestrogens can influence goitrogenesis and hyperplasia in PBF-Tg mice, thus implicating a role for
phytoestrogens in modulating thyroid disease. 1
Read ML et al., (2011)
Cancer Research 71(19), 6153–6164.
Original languageEnglish
Article numberP196
JournalThyroid
Volume22(1_Suppl)
Publication statusPublished - 2012
Event82nd Annual Meeting of the American Thyroid Association - Quebec City, Canada
Duration: 19 Sep 201223 Sep 2012

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