Synergistic signaling of KRAS and thyroid hormone receptor β mutants promotes undifferentiated thyroid cancer through MYC up-regulation.

Undifferentiated thyroid carcinoma is one of the most aggressive human cancers with frequent RAS mutations. How mutations of the RAS gene contribute to undifferentiated thyroid cancer remains largely unknown. Mice harboring a potent dominant negative mutant thyroid hormone receptor β, TRβPV (Thrb(PV/PV)), spontaneously develop well-differentiated follicular thyroid cancer similar to human cancer. We genetically targeted the Kras(G12D) mutation to thyroid epithelial cells of Thrb(PV/PV) mice to understand how Kras(G12D) mutation could induce undifferentiated thyroid cancer in Thrb(PV/PV)Kras(G12D) mice. Thrb(PV/PV)Kras(G12D) mice exhibited poorer survival due to more aggressive thyroid tumors with capsular invasion, vascular invasion, and distant metastases to the lung occurring at an earlier age and at a higher frequency than Thrb(PV/PV) mice did. Importantly, Thrb(PV/PV)Kras(G12D) mice developed frequent anaplastic foci with complete loss of normal thyroid follicular morphology. Within the anaplastic foci, the thyroid-specific transcription factor paired box gene 8 (PAX8) expression was virtually lost and the loss of PAX8 expression was inversely correlated with elevated MYC expression. Consistently, co-expression of KRAS(G12D) with TRβPV upregulated MYC levels in rat thyroid pccl3 cells, and MYC acted to enhance the TRβPV-mediated repression of the Pax8 promoter activity of a distant upstream enhancer, critical for thyroid-specific Pax8 expression. Our findings indicated that synergistic signaling of KRAS(G12D) and TRβPV led to increased MYC expression. Upregulated MYC contributes to the initiation of undifferentiated thyroid cancer, in part, through enhancing TRβPV-mediated repression of the Pax8 expression. Thus, MYC might serve as a potential target for therapeutic intervention.

Zhu X ，Zhao L ，Park JW ，Willingham MC ，Cheng SY ... -  《NEOPLASIA》

Activation of integrin-ERBB2 signaling in undifferentiated thyroid cancer.

Zhu X ，Zhu YJ ，Kim DW ，Meltzer P ，Cheng SY ... -  《American Journal of Cancer Research》

Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model.

New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the ThrbPV/PVKrasG12D mouse, a model of anaplastic thyroid cancer. We treated ThrbPV/PVKrasG12D mice with vehicle or JQ1 at a dose of 50 mg/kg body weight/day starting at the age of 8 weeks for a 10-week period and monitored thyroid tumor progression. JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation. These preclinical findings suggest that BET inhibitors may be an effective agent to reduce thyroid tumor burden for the treatment of refractory thyroid cancer. Clin Cancer Res; 23(2); 430-40. ©2016 AACR.

Zhu X ，Enomoto K ，Zhao L ，Zhu YJ ，Willingham MC ，Meltzer P ，Qi J ，Cheng SY ... -  《-》

Activation of tumor cell proliferation by thyroid hormone in a mouse model of follicular thyroid carcinoma.

Lu C ，Zhu X ，Willingham MC ，Cheng SY ... -  《-》

Role of TSH in the spontaneous development of asymmetrical thyroid carcinoma in mice with a targeted mutation in a single allele of the thyroid hormone-β receptor.

Zhao L ，Zhu X ，Won Park J ，Fozzatti L ，Willingham M ，Cheng SY ... -  《-》