Thyroid cancers are the most common
malignancy of the endocrine system in humans. To understand the molecular genetic events underlying thyroid
carcinogenesis, we have generated a mouse model that spontaneously develops
follicular thyroid carcinoma similar to human
thyroid cancer (Thrb(PV/PV) mouse). This mutant mouse harbors a dominant-negative mutated
thyroid hormone receptor β (denoted PV). The PV mutation was identified in a patient with resistance to
thyroid hormone (TH). Thrb(PV/PV) mice exhibit highly elevated serum
thyroid-stimulating hormone levels and increased TH. We have previously shown that
thyroid-stimulating hormone is required, but not sufficient to induce metastatic
follicular thyroid cancer in Thrb(PV/PV) mice. However, whether the elevated TH also contributes to the thyroid
carcinogenesis of Thrb(PV/PV) mice was not elucidated. To understand the role of TH in thyroid
carcinogenesis, we blocked the production of TH by treating Thrb(PV/PV) mice with
propylthiouracil (Thrb(PV/PV)-PTU mice) and compared the development of
thyroid cancer in Thrb(PV/PV)-PTU and untreated Thrb(PV/PV) mice. We found that thyroid
tumor growth was reduced by ∼42% in Thrb(PV/PV)-PTU mice as compared with Thrb(PV/PV) mice. Analysis by
bromodeoxyuridine-nuclear labeling showed decreased incorporation of
bromodeoxyuridine in thyroid
tumor cells of Thrb(PV/PV)-PTU mice, indicative of decreased
tumor cell proliferation. However, cleaved-
caspase 3 staining showed no apparent changes in apoptosis of
tumor cells in Thrb(PV/PV)-PTU mice. Molecular studies identified a marked attenuation of the PI3K-AKT-β-catenin signaling pathway that led to decreased
protein levels of
cyclin D2, thereby decreasing
tumor cell proliferation in Thrb(PV/PV)-PTU mice. Furthermore,
matrix metalloproteinase-2, a downstream target of β-
catenin and a key regulator during
tumor invasion and
metastasis, was also decreased. Thus, the present study uncovers a critical role of TH in promoting the thyroid
carcinogenesis of Thrb(PV/PV) mice via membrane signaling events. Importantly, these findings suggest that anti-thyroid drugs could be considered as possible therapeutic agents of
thyroid cancer.