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Annals of Clinical & Laboratory Science 31:245-252 (2001)
© 2001 Association of Clinical Scientists

Nuclear Localization of Thyroid Transcription Factor-1 Correlates with Serum Thyrotropin Activity and May Be Increased in Differentiated Thyroid Carcinomas with Aggressive Clinical Course

Cydney L. Fenton1,4, Aneeta Patel2, Henry B. Burch3, R. Michael Tuttle5 and Gary L. Francis1,4
Departments of Pediatrics,1 Clinical Investigation,2 and Medicine,3 Walter Reed Army Medical Center, Washington, District of Columbia; 4 Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland; and 5 Department of Endocrinology, Memorial Sloan Kettering Cancer Center, New York, New York.

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or to reflect the opinions of the Uniformed Services University of the Health Sciences, the Department of the Army, or the Department of Defense. Address correspondence to Gary L. Francis, M.D., Ph.D., Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA; tel 301 295 9716; fax 301 295 3898; e-mail gfrancis{at}usuhs.mil.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Thyroid transcription factor 1 (TTF-1) is essential for thyroid differentiation and regulates expression of thyroglobulin, thyroid peroxidase, sodium/iodide symporter, and thyrotropin receptor (TSH-R) genes. Because thyrotropin (TSH) upregulates these same genes, we hypothesized TSH-R activation might increase TTF-1 and that TTF-1 might be differentially expressed in benign and malignant thyroid disease. TTF-1 expression and sub-cellular localization were determined by immunohistochemistry in 62 thyroid carcinomas, 15 benign lesions, and 2 normal thyroids. Nuclear TTF-1 was detected in benign (77%) and malignant lesions (69%), with similar intensity in both (1.1 ± 0.19 versus 1.0 ± 0.10). Nuclear TTF-1 staining correlated with the effective serum TSH level (p = 0.02) and patient age (p < 0.05). Nuclear TTF-1 was detected in 35 papillary thyroid carcinomas (PTC), of which 23% developed recurrent or persistent disease, and was absent from 18 PTC, of which only 6% recurred (p = 0.06). We conclude that nuclear TTF-1 correlates with serum TSH activity, increases with age, and may be increased in persistent or recurrent PTC.

(received 20 March 2001; accepted 15 May 2001)

Keywords: Thyroid transcription factor (TTF-1), thyrotropin (TSH), thyroid cancer, immunohistochemistry


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
The homeodomain containing phosphoprotein thyroid transcription factor -1 (TTF-1), also known as thyroid specific enhancer-binding protein (T/EBP), is essential for embryonic development and function of the thyroid [1–5]. TTF-1 is tissue specific, and expressed only in thyroid, lung, and diencephalon [1,6,7]. T/EBP-null mice lack thyroid and pituitary glands and have developmental defects in the lung and hypothalamus [1,3]. In the fetus, TFF-1 expression occurs early during organogenesis and is responsible for induction of the differentiated thyroid phenotype [8,9]. TTF-1 is transcriptionally active in the human thyroid and is present in the nucleus of thyroid follicular cells [7]. Along with other transcription factors, TTF-1 is considered to be a major switch in the regulation of thyroid gene expression [2,3,8,10,11]. In the mature thyroid, TTF-1 regulates gene expression for thyroglobulin (Tg), thyroperoxidase (TPO), thyrotropin receptor (TSH-R), and the sodium-iodide symporter (NIS) [1–5,9,12].

TTF-1 is post-translationally modified by protein kinase A (PKA) [13]. Phosphorylated TTF-1, in association with the human paired box protein-8 (Pax8), binds to the Tg promoter and induces transcription of the Tg gene [13]. Ohmori et al [10] showed that TTF-1 increases TSH-R gene expression by a specific interaction with the up-stream TTF-1 binding site. An intact down-stream TTF-1 binding site is also required [10].

TSH is known to regulate the function and growth of the thyroid and several observations suggest a potential interaction between TSH and TTF-1 [8]. TSH, thyrotropin receptor antibodies (TRAb), and insulin independently stimulate the expression of Tg mRNA, which is also regulated by TTF-1 [1,3,5,8,10,11]. TTF-1 binding activity is reduced by oxidation, and thyroid tissue redox state is directly controlled by TSH [4,14]. Joba et al [2] showed that patients with Graves disease have increased levels of TTF-1 mRNA in the thyroid. However, attempts to define direct control of TSH over TTF-1 resulted in opposite conclusions. TTF-1 mRNA was transcriptionally downregulated by TSH in FRTL-5 cells and TTF-1 mRNA levels eventually decreased following exposure to TSH or adenosine 3':5'-cyclic monophosphate (cAMP) in FRTL-5 cells [8,10,13].

The functional interplay between TSH and TTF-1 in differentiated thyroid carcinoma is controversial. TTF-1 is absent from anaplastic thyroid carcinomas with reduced Tg expression, decreased in less well differentiated papillary (PTC) or follicular (FTC) thyroid carcinomas, but expressed in well differentiated thyroid adenomas [13,15]. De Vita et al [6] showed that thyroid cancer cells containing the ret/PTC-1 oncogene have reduced Tg and TPO mRNA levels. They also showed that the ret/PTC-1 oncogene disrupts the thyroid differentiated phenotype by impairing the function of TTF-1 at the post-translational level [6].

To our knowledge, only one previous study has examined benign and malignant thyroid tumors for the nuclear localization of TTF-1 [16]. Katoh et al [16] detected TTF-1 nuclear staining in 15 benign follicular adenomas, 5 FTC, and 13 PTC. All but 2 of 13 PTC also had detectable TTF-1 mRNA. In contrast, TTF-1 was absent from 3 of 4 undifferentiated thyroid carcinomas. There was no significant relationship between the presence of nuclear TTF-1 staining and the expression of either Tg or TPO genes, and no clinical details were provided regarding the risks for recurrence of any of the tumors.

Because of the critical roles of TTF-1 in thyroid gene transcription and in maintaining the differentiated thyroid phenotype, we designed this study to test the hypothesis that TTF-1 is increased by stimulation of the TSH-R, differentially expressed in benign and malignant conditions of the thyroid, and related to the outcome of individual tumors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
This study was approved by the Institutional Review Board and the Human Use Committee of the Department of Clinical Investigation at Walter Reed Army Medical Center. We studied 79 patients, including 53 with PTC, 9 with FTC, 15 with benign thyroid diseases (7 benign follicular nodules, 4 Graves disease, 2 multinodular goiter, 2 Hashimoto thyroiditis), and 2 normal thyroid controls. The clinical details of each patient were obtained from a computerized database previously published by our group [17]. The extent of disease at diagnosis was defined according to DeGroot et al [18]. Briefly, class I disease was confined to the thyroid gland, class II included regional lymph node involvement, class III extended beyond the thyroid capsule or was inadequately resected, and class IV showed distant metastasis. Recurrence was defined as the appearance of new disease (new radioactive iodine uptake or biopsy proven disease) in any patient who had been free of disease for at least 4 mo (no palpable disease and negative 131I scan) [17]. Patients were classified as having persistent disease if they were at least 4 mo beyond initial treatment and had persistent 131I uptake, MRI evidence of disease, or elevated serum Tg despite prior surgery and 131I-ablation [17].

Effective TSH levels were defined as elevated if either the serum TSH or the TSH-R antibody levels (for patients with Graves disease) were elevated. TSH levels were defined as normal if the serum TSH level was in the normal range (0.5 to 5.0 mU/ml, third generation chemiluminescent assay, Nichols Institute, San Juan Capistrano, CA). The TSH level was classified as suppressed if the serum TSH was < 0.5 mU/ml and the TSH-R antibody (thyroid stimulating immunoglobulin (TSIG)) test was also negative.

Original, formalin-fixed, paraffin-embedded tissue blocks were sectioned and stained with hematoxylineosin for routine histology [19]. The diagnosis was confirmed using these sections, and the sections (5µm) immediately adjacent were removed and stained for TTF-1. Slides were deparaffinized and rehydrated through a series of graded alcohols and water. TTF-1 antigen was retrieved with citrate buffer (pH 6, 30 min, microwave/pressure cooker).

The slides were incubated (30 min, 37°C) with Lab Probe tissue blocker (Biomeda Corporation, Foster City, CA) to block non-specific binding. Primary anti-human TTF-1 antibody (1:25 v/v, 1 hr, 37°C, Neomarkers, Union City, CA) was then added, followed by secondary biotinylated goat anti-rabbit immunoglobulin (IgG, 30 min, 37°C, Lab Probe Kit, Biomeda Corporation). Sections were treated with preformed streptavidin biotin complex, horseradish peroxidase, and diamino-benzidine chromogen (DAB, Lab Probe Kit, Biomeda Corporation). Slides were counter-stained with hematoxylin. Negative controls included pre-absorption of the primary antibody with synthetic TTF-1 peptide (Santa Cruz Biotechnology, Santa Cruz, CA) as well as deletion of the primary and secondary antibodies. Normal thyroid and lung were used as positive controls.

The intensity of nuclear TTF-1 staining was determined by two blinded, independent examiners. Nuclear staining was quantified as grade 0 (absent), grade 1 (minimal), grade 2 (moderate), or grade 3 (intense), based on the staining characteristics of the majority of the tumor. The interobserver concordance was >95%. For a few sections with disparate readings, a third examiner reviewed the slides and the 2 concordant scores were used to assign the final grade. Specificity of the staining methods was demonstrated using 3 negative controls. TTF-1 staining was completely blocked by pre-adsorption of the antisera with TTF-1 specific peptide, deletion of the primary antibody, and deletion of the secondary antibody.

Statistical analyses were performed using the SPSS software for Windows 95. Mean values were compared using analysis of variance (ANOVA), correlations were performed using Pearson correlation, and survival data were compared using Kaplan Meier survival curves with log rank comparison. Non-parametric analyses included the Chi square and Fisher’s exact test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
The clinical details and results of nuclear TTF-1 expression for patients with PTC are listed in Table 1Go. The patients with PTC (39 female, 14 male) had a mean age of 19.5 ± 6.9 yr (range 6–40), a mean tumor size of 2.0 ± 1.4 cm (range 0.5–7.5), and a mean follow-up of 4.5 ± 3.7 yr (range 0–14.1). Follow-up exceeded 1 yr in 83%, and 6 yr in 42% of patients. Only one patient had previous radiation exposure.


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  		Table 1. Characteristics, risk of persistent or recurrent papillary thyroid carcinoma (PTC), and nuclear TTF-1 expression.
 
The clinical details and results of nuclear TTF-1 expression for patients with FTC are listed in Table 2Go. The patients with FTC (7 female, 2 male) had a mean age of 18.2 ± 2.7 yr (range 13–21), a mean tumor size of 2.5 ± 1.5 cm (range 0.2–4.5), and a mean follow up of 4.9 ± 3.7 yr (range 1.6–14). No patient with FTC had previous radiation exposure. The demographics of both groups are similar to those of our larger series, which was published previously [17].


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  		Table 2. Characteristics, risk of persistent or recurrent follicular thyroid carcinoma (FTC), and nuclear TTF-1 expression.
 
The different grades of nuclear TTF-1 staining (grade 0–3) are shown in Fig. 1Go. Representative sections from several tissue blocks are shown, and were not necessarily obtained from the same subjects. Fig. 2Go shows the results of nuclear TTF-1 expression for patients with PTC compared to FTC and non-malignant thyroid tissue (normal thyroid plus benign thyroid diseases). Nuclear TTF-1 expression was similar in PTC (mean intensity 0.9 ± 0.11, p = 0.4) and FTC (1.2 ± 0.22, p = 0.8), compared to non-malignant thyroid lesions (1.1 ± 0.22). In 2 normal thyroids, the nuclear TTF-1 staining grade was 1; these results are included in the benign category on Fig. 2Go. Fig. 3Go shows the results of nuclear TTF-1 staining for benign thyroid lesions, categorized by diagnosis. Nuclear TTF-1 staining was similar in all groups.






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  		Fig. 1 shows the different intensities of nuclear TTF-1 staining. Panel A: absent, grade 0; panel B: slight, grade 1; panel C: moderate, grade 2; and panel D: intense, grade 3; (200x).

 


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  		Fig. 2 compares the intensity of TTF-1 nuclear staining in benign thyroid disease with differentiated thyroid carcinomas (PTC and FTC). The data are presented as mean ±SEM; no significant differences in TTF-1 nuclear staining were observed among the groups.

 


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  		Fig. 3 compares the intensity of TTF-1 nuclear staining in benign thyroid disorders (NL, normal thyroid; MNG, multinodular goiter). The data are presented as mean ±SEM; no significant differences in TTF-1 nuclear staining were observed among the groups.

 
Fig. 4Go shows the relationship between nuclear TTF-1 staining intensity and the effective serum TSH level. There was a significant increase in nuclear TTF-1 staining intensity as the effective TSH level increased (r = 0.43, p = 0.02). This relationship was significant for both malignant and non-malignant tissues.



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  		Fig. 4 shows significant increase in nuclear TTF-1 staining with increasing levels of effective TSH (analysis of trend, r = 0.43, p = 0.02). Effective TSH was defined either as an elevated serum TSH level, or elevated thyroid stimulating immunoglobulin and suppressed TSH level in patients with Graves disease.

 
Fig. 5Go shows the relationship between nuclear TTF-1 expression and the age of all patients. Nuclear TTF-1 staining intensity increased significantly with age (r = 0.25, p <0.05). To eliminate any confounding effect from diagnosis, patients with PTC were analyzed separately. Nuclear TTF-1 staining intensity still increased significantly with age (r = 0.29, p = 0.035) for the patients with PTC. There were no significant relationships between nuclear TTF-1 expression and the extent of disease at diagnosis, tumor focality, size, or patient gender. We previously studied ret/PTC-1 gene rearrangements in 30 of the PTC patients included in the current study [20]. The mean TTF-1 staining intensity (0.67 ± 0.24) for 9 PTC with ret/PTC-1 mutations was similar to 21 PTC that did not have ret/PTC-1 mutations [0.81 ± 0.15, p = 0.6] [20].



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  		Fig. 5 shows a significant increase in nuclear TTF-1 staining intensity with increasing patient age for all patients (r = 0.25, p < 0.05). The equation of the regression line is Y = 0.033X + 0.335.

 
The impact of nuclear TTF-1 expression by the primary tumor on the risk of recurrence was investigated for patients with PTC and FTC. As shown in Table 1Go, recurrent or persistent disease developed mainly for PTC that expressed nuclear TTF-1. Eight of 35 patients (23%) with nuclear TTF-1 expression developed recurrent or persistent disease compared to 1 of 18 patients (6%) who failed to express nuclear TTF-1. The number of patients with recurrent or persistent disease was too small to show statistical significance (p = 0.06, Fisher’s exact test). The impact of nuclear TTF-1 staining on recurrence was not based on an effect of age. The average age of patients with recurrent disease (20.7 ± 10.2 yr, range 6–40) was similar to that of patients who did not develop recurrent disease (19.0 ± 5.4 yr, range 6 – 35).

Recurrence data for the 9 patients with FTC are shown in Table 2Go. Recurrent disease developed in 1 of 8 patients (12.5%) who showed nuclear TTF-1 expression. Only 1 patient failed to express TTF-1 and that patient remained free of disease during 43 mo of follow-up. The total number of patients with FTC was too small to derive conclusions about nuclear TTF-1 expression in FTC.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
Based on the essential roles of TTF-1 in thyroid gene transcription and maintenance of the differentiated thyroid phenotype, we designed this study to examine the sub-cellular localization of TTF-1 in a variety of pathological thyroid conditions and to determine the effect of TTF-1 expression on the clinical behavior of thyroid carcinoma. In addition, since TSH upregulates NIS, TPO, and TG gene expression, we hypothesized that TTF-1 might be increased in response to activation of the TSH-R.

We observed a direct correlation between the effective serum TSH level and the nuclear localization of TTF-1. This observation is supported by previous studies [2,11]. Using Northern blot analysis, Schuppert et al [11] showed that TSH-R expression was increased in Graves disease and that TTF-1 mRNA levels were positively correlated with TSH-R gene expression. They were unable to show any direct increase in TTF-1 mRNA levels in Graves thyroid tissue. However, Joba et al [2] did find that TTF-1 gene expression was markedly elevated in Graves glands compared to other thyroid conditions. A study by van der Kallen et al [13]revealed a more complex relationship between TSH, TSH-R, and TTF-1. Using FRTL-5 cells, they showed that TSH downregulated the levels of both TSH-R and TTF-1 mRNA by 4 hr. However, this was preceeded by a transient increase in TSH-R mRNA levels [13]. Their observation does not support our direct link between effective TSH levels and nuclear TTF-1 staining. There are many possible explanations for this difference. First, our study examined TTF-1 protein expression, whereas van der Kallen et al [13] measured TTF-1 mRNA levels. Differences in the rate of transcription, mRNA stability, translational control, or post-translational modification could account for this disparity. Another important difference is that we examined the sub-cellular localization of TTF-1. Only TTF-1 in the nuclear compartment correlated with effective TSH levels or the risk of recurrent disease. Cytoplasmic TTF-1 was detected in some of our samples, but did not correlate with nuclear TTF-1 or clinical outcome. Our data suggest that nuclear localization of TTF-1 is physiologically important and that nuclear TTF-1 localization is controlled by more than TTF-1 gene transcription.

Differentiated thyroid carcinomas maintain a differentiated phenotype that includes iodine uptake and Tg synthesis but are less efficient than the normal thyroid [15]. Oncogenes are believed to disrupt this process by interfering with the transcription of tissue-specific differentiation factors [15]. Previous studies suggest TTF-1 expression may be disrupted by malignant transformation of the thyroid. In support of this theory, the expression of Tg and TTF-1 are both reduced in anaplastic thyroid carcinomas [20,21]. For these reasons, we supposed that TTF-1 might be differentially expressed in benign and malignant thyroid disease, but our results do not support this hypothesis. Nuclear TTF-1 expression was present in 77% of benign and 69% of malignant lesions, and was of similar intensity for both (1.1 ± 0.19 versus 1.0 ± 0.10, p = 0.59). This could be due to the fact that we studied only well-differentiated thyroid carcinomas. Had anaplastic thyroid cancers been included in our study, TTF-1 expression might have differed between benign and malignant disease. Our results are similar to those of Katoh et al [16], who also detected TTF-1 nuclear staining in the over-whelming majority of benign and well-differentiated malignant thyroid tumors. In their study, 3 of 4 poorly-differentiated thyroid tumors did not express TTF-1. Taken together, these observations suggest that nuclear TTF-1 is preserved in both benign and well-differentiated malignant tumors.

Among the well-differentiated carcinomas in our study, there was a suggestion that recurrent or persistent disease developed mainly for PTC or FTC that expressed nuclear TTF-1. Thus, 23% (8 of 35) of PTC and 12.5% of FTC (1 of 8) that contained nuclear TTF-1 developed recurrent or persistent disease. Only 6% (1 of 18) of patients with PTC that did not express nuclear TTF-1 developed a recurrence (p = 0.06). The impact of nuclear TTF-1 staining on recurrence cannot be explained by confounding differences in patient age. The average age for patients with recurrence disease (20.7 ± 10.2 yr) was similar to that of patients who did not develop recurrent disease (19.0 ± 5.4 yr). To our knowledge, these findings are unique and offer the first indication that nuclear TTF-1 may be important in promoting recurrence of well-differentiated thyroid carcinoma. This observation is indirectly supported by many previous studies that show a reduced risk for recurrent disease among patients managed by TSH suppression [22–29]. Since TTF-1 increases TSH-R expression, it would follow that tumors expressing TTF-1 would have increased expression of TSH-R and increased recurrence from TSH stimulation. Our findings are consistent with these hypotheses, but are counter-intuitive to the observation that TTF-1 is absent from anaplastic thyroid carcinoma [20,21]. It is possible, however, that anaplastic thyroid cancer has become independent of growth factor regulation, including TSH. If so, one would not expect TTF-1 to have an effect on the recurrence of anaplastic thyroid cancer.

Another oncogene, ret/PTC-1, is hypothesized to play an important role in the pathogenesis of PTC. De Vita et al [6] showed that the ret/PTC-1 oncogene disrupts the expression of the differentiated thyroid phenotype. They hypothesized that this could arise from impaired function of TTF-1 and Pax8. We have previously reported on the incidence of ret/PTC-1 mutations in these same thyroid cancer samples, but we did not find any significant correlation between TTF-1 expression and the presence or absence of ret/PTC-1 mutations [20]. However, we did not examine Pax8 expression, and it is possible that we failed to detect any difference because Pax8 might also be involved in the regulation of TTF-1.

In conclusion, TTF-1 protein expression is detected in the nucleus of the majority of benign thyroid diseases and well differentiated thyroid carcinomas. Nuclear TTF-1 localization correlates with the effective serum TSH level and may be increased in the PTC and FTC that are destined for recurrence.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
The authors thank David Jackson and Richard Terrell for help in slide preparation and processing and Robin Howard for help with statistical analyses.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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