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Treatment with LT4 is used to suppress thyrotropin levels after the management of differentiated thyroid cancers after surgery, with doses and targets for thyrotropin (thyroid-stimulating hormone, TSH) determined by the risk of cancer recurrence determined in the individual patient. Moreover, the role of thyroid hormones and their receptors in the initiation—and, potentially, cure—of a range of cancer types is an active area of research.
1 Introduction
1.1 Overview of the Management of Differentiated Thyroid Cancer
In general, the treatment of differentiated thyroid cancers (DTC) consists of surgery, post-operative/adjuvant radioactive iodine (RAI, 131I) treatment and hormonal therapy with levothyroxine (LT4) [1, 2]. Surgery is the standard intervention for the management of DTC (although the management of microcancers of the thyroid remains a matter of debate) [1, 2]. Where the patient receives a total thyroidectomy, the resulting athyroid state induces a severe hypothyroidism that causes thyrotropin (TSH) to rise to high levels, typically at least 30 IU/mL after several weeks (compared with the usual upper limit of the normal reference range of about 4 mIU/L) [3].
For papillary or follicular thyroid tumours, the high TSH level stimulates any remaining unresectable thyroid tissue or metastatic tumour cells that retain some endocrine activity to take up iodine from the circulation [3]. Treatment with RAI is then administered periodically over a period of years and the RAI is taken up avidly by these cells resulting in their irradiation and ablation: in this way, the majority of these cancers can be eradicated successfully [1, 3]. Injections of recombinant human TSH may also be used to increase RAI uptake of residual thyroid cancer cells [3, 4].
Patients may require lifelong substitution of LT4 after thyroid surgery for DTC, depending on the amount of thyroid tissue removed [3, 5]. Moreover, high-risk patients may receive TSH-suppressive therapy with LT4. The decision on whether to aim for full suppression of TSH (TSH < 0.1 mIU/L), or partial TSH suppression (TSH 0.1–0.4 mIU/L) should be personalised [2, 3].
1.2 Scope of This Chapter
This chapter reviews the benefits and risks associated with LT4-suppressive therapy in patients who have undergone surgery and RAI for DTC. The diagnosis of thyroid cancer, tumour staging, allocation of patients to different modalities of surgery and their outcomes, and the application, effectiveness of and development of refractoriness to RAI per se are beyond its scope and will not be discussed further here (we refer the reader to current guidelines in these areas [1, 3, 5, 6]). In addition, the consequences of long-term suppressive LT4 administration for bone homeostasis and health in these patients are considered in chapter “Levothyroxine and Bone” of this book, and are also not discussed in detail here. Chapter “Levothyroxine and the Heart” of this book reviews the effects of TSH-suppressive doses of LT4 on the heart. Finally, medullary thyroid tumours arise from calcitonin-secreting parafollicular cells (C-cells) that do not secrete thyroxine: these patients are not treated with RAI and LT4 and their management is also not addressed here [7].
2 Application of Thyrotropin-Suppressive Doses of Levothyroxine After Surgery and Radioactive Iodine for Well-Differentiated Thyroid Tumours
2.1 Need for Suppression of Thyrotropin in Thyroid Cancer Survivors
TSH promotes the growth of thyroid tumours, and levels of this hormone are suppressed in the initial period following surgery for many DTC. A meta-analysis supports the effectiveness of this approach in improving long-term clinical outcomes post-thyroidectomy, compared with patients who did not receive TSH-suppressive therapy [8]. However, it has become clear in recent years that stringent suppression of TSH does not improve long-term clinical outcomes in patients with other than high-risk presentations of well-differentiated thyroid cancer [9,10,11,12,13]. Accordingly, patients with thyroid cancer assessed as being at lower risk of disease recurrence do not require complete suppression of TSH. This approach is designed to optimise the balance between suppression of disease recurrence (benefit) and the potential for adverse effects on bone [9].
For adults, the level of thyroglobulin has been found to be strongly predictive of the risk of recurrent disease (see Fig. 1a) [14], and thus different targets for TSH suppression are provided in guidelines for low-risk patients according to their post-surgery thyroglobulin levels [1, 3]. A recent meta-analysis has confirmed the diagnostic and prognostic power of thyroglobulin measurement during post-thyroidectomy TSH suppression using LT4, with negative predictive value for ruling out evidence of structural thyroid carcinoma in excess of 99% [15]. The relationship between thyroglobulin and post-surgical outcome is less well understood in children, for whom targets for TSH suppression are accordingly not stratified formally according to the thyroglobulin level [3].
2.2 Long-Term Consequences of Thyroidectomy and Thyrotropin Suppression
TSH-suppressive LT4 therapy induces a thyroid hormone status that is broadly equivalent to subclinical hyperthyroidism [13]. Overt hyperthyroidism during LT4-suppressive therapy should be avoided. Accordingly, care must be taken to achieve a balance between the achievement of adequate suppression of TSH levels to optimise cancer-free survival, with the potential adverse effects associated with subclinical hyperthyroidism [16]. Clinical studies in patients who have received LT4-based TSH-suppressive therapy have revealed several areas of concern or benefit, which are described briefly below.
2.2.1 Bone
Untreated longstanding hyperthyroidism is associated with loss of bone mineralisation, osteoporosis and increased risk of fractures. Studies in TSH-suppressed populations have been conflicting, but some studies have demonstrated increased osteoporosis and fracture risk associated with LT4 treatment (reviewed in chapter “Levothyroxine and Bone” of this book).
2.2.2 The Cardiovascular System
A retrospective study from the Korean National Health Insurance database, which covers 97% of people in that country, evaluated the risk of coronary heart disease (CHD) and ischemic stroke over a follow-up period of 4.3 years in 182,419 patients following thyroidectomy for differentiated thyroid cancer [17]. Higher hazard ratios for CHD and stroke were found for the thyroidectomised population, relative to propensity score-matched controls. The signal for adverse cardiovascular outcomes became stronger at doses of LT4 that were higher than 115–144 μg/day. Although atrial fibrillation was more common in patients receiving higher doses of LT4, this was associated with only 4% of strokes. As expected, cardiovascular risk factors increased the risk of CHD or stroke. Another chart review in thyroid cancer survivors found no association between up to 9 years of over-suppression of TSH with LT4 (according to guideline recommendations based on risk of thyroid cancer recurrence) and adverse cardiovascular outcomes, but this study only contained 14 subjects [18]. Chapter “Levothyroxine and the Heart” of this book reviews the effects of LT4 on the heart.
2.2.3 Patient-Reported Outcomes
Fatigue is often reported as a long-term complication of thyroidectomy and subsequent TSH suppression [19]. One study showed that the persistence of residual symptoms reminiscent of hypothyroidism on TSH-suppressive therapy were correlated with a low level of FT3 [20]. Altering the dose of TSH, or switching to a combination of LT4 and T3 administration did not induce a clear improvement of fatigue, however [21, 22]. Current guidelines for the management of hypothyroidism recommend that LT4 remains the first-line treatment. Exercise appears to be an effective way of combating fatigue and improving the quality of life in this setting [21, 23]. A similar benefit was observed in LT4-treated breast cancer patients undergoing chemotherapy [24]. More clinical studies of this relatively common, and potentially disabling, complication of thyroid cancer management are needed [21].
3 Thyroid Hormones and Cancer Risk
Variations in thyroid hormones have been associated with changes in the risk of a wide range of cancer types [25]. Examples of effects of thyroid hormones on the risk of various tumour types in epidemiological studies are shown below. However, the results are often conflicting and have to be judged cautiously since association does not prove causation.
Thyroid:
Observational data have associated an increased circulating level of TSH with an increased risk of developing differentiated thyroid cancer [26, 27] and/or a more advanced stage of this tumour at presentation [26]. Other studies found that low TSH increased the risk of thyroid cancer [14], that high TSH in men, but low TSH in women, was associated with thyroid cancer [28], or that the influence of abnormal TSH on cancer risk was amplified in non-diabetic subjects with higher levels of fasting serum glucose [29]. Fig. 1 shows the risk of cancer associated with thyroid nodules at different levels of TSH and other markers of thyroid homeostasis from two of these observational studies. Higher TSH levels were associated with a lower risk of incident differentiated thyroid cancer in one study (Fig. 1a) [14], while increases in TSH levels within the normal reference range increased thyroid cancer risk in the other study, in patients with thyroid nodules (Fig. 1b) [26].
Breast:
Hyperthyroidism (high TT4 or FT4 and/or low TSH) has been associated with increased risk of breast cancer in some observational studies [30,31,32]. This association was shown to extend into the euthyroid range [33], and to be present pre- and post-menopause [34]. There was no effect of variation of TSH in other studies [31, 35], and the impact of anti-thyroid antibodies on breast cancer risk was variable [30,31,32]. A meta-analysis of 8 cross-sectional studies found a positive association between elevated T4, T3, anti-thyroid peroxidise antibodies and anti-thyroglobulin antibodies and the prevalence of breast cancer [36]. Likewise, autoimmune thyroiditis has been found to be more common in women with vs. without breast cancer [37].
A population-based case-control study from Taiwan (65,491 breast cancers, 261,964 controls) found that LT4 administration vs. no LT4 use was associated with a modestly higher risk of breast cancer, with a greater effect in older (≥65 years) patients (odds ratio [OR] 1.45 [95%CI 1.23–1.71], p < 0.01) compared with younger patients (OR 1.19 [95%CI 1.09–1.29], p < 0.01) [38]. However, the ORs were similar for patients who received LT4 for ≤1 year (1.22) and >1 year (1.26), and further study is required to confirm this association.
Prostate:
Low TSH/high T4 increased the risk of prostate cancer in a population-based observational study [30]. Conversely, and consistent with this study, high TSH was protective against prostate cancer in the population of a clinical trial conducted to answer a clinical question that was unrelated to thyroid function [39].
Gastrointestinal:
A population-based study found no effect of TSH or FT4 levels on colorectal cancer risk [30]. However, high FT4, but not a diagnosis of hypothyroidism or hyperthyroidism, predicted shorter survival in a cohort of 258 patients with advanced gastro-oesophageal cancer [40]. Low FT3 was associated with prolonged survival in this study, which is difficult to reconcile with the adverse effect of high FT4 [40].
A large population-based case-control study from a UK general practice database (The Health Improvement Network, 20,990 colorectal cancer cases and 82,054 controls) found that both hyperthyroidism and untreated hypothyroidism predicted an increased risk of having colorectal cancer [41]. Long-term treatment with LT4 was associated with a reduced risk of colorectal cancer, with a lower risk for a longer treatment duration [41].
Liver:
Higher TSH was associated with larger tumours in a cohort of 838 patients with advanced hepatocellular carcinoma, and higher FT4 (≥16.6 ng/L) predicted poorer survival vs. lower levels of FT4 [42].
Pancreas:
A retrospective study found that survival with pancreatic cancer did not vary according to hypothyroid or euthyroid status overall, but that hypothyroid patients taking LT4 demonstrated higher tumour stage, and more localised and distant tumour spread than euthyroid patients [43]. However, this study is difficult to interpret, as there were only 71 hypothyroid patients included, and there was no information presented on how many were taking LT4 [43].
Table 1 summarises briefly some potential mechanisms that have been demonstrated in clinical or experimental studies to explain an association between thyroid hormone status and tumorigenesis [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67]. Thyroid hormones mediate their effects on the cancer cell through several non-genomic pathways including activation of integrin avβ3 promoting metastasis and angiogenesis within tumours. Furthermore, cancer development and progression are affected by dysregulation of local bioavailability of thyroid hormones and thyroid hormone receptor changes [25, 45, 49, 68,69,70].
Tetraiodothyroacetic acid may oppose these actions [69]. The thyroid receptor, TRβ is downregulated in many tumours, and activation of this receptor has been proposed as a strategy for increasing the sensitivity of triple-negative breast cancer cells to chemotherapy [71].
Ovarian cancer is a highly metastatic tumour, and several thyroid hormone analogues exerted cytotoxic effects in ovarian cancer cell lines, probably by antagonising the effects of thyroid hormones on the integrin αvβ3 axis [72] A similar phenomenon has been observed in thyroid and lung cancer cells, among others [49, 51, 52, 69]. Tetraiodothyroacetic acid, a metabolite of T4, may reduce the resistance of cancer cells to radiotherapy [73]. Deiodinases modulate the local bioavailability of thyroid hormones, by controlling T4 conversion to T3 and other thyroid hormone derivatives and this expression of these enzymes differs in a range of tumour types, compared with non-neoplastic tissues [74, 75]. These observations provide promising avenues for future research on the development of novel anticancer agents.
4 Conclusions
Observational data have implicated variations in the levels of thyroid hormones with variations in the risk of a range of cancer types, including of the thyroid itself. This association extends to within the currently accepted “normal” range for thyroid hormones. In addition, the discovery of novel interactions between thyroid hormones and receptors both inside cells and in the extracellular space have opened up new avenues for anticancer research. Treatment with suppressive doses of LT4 is one of the key components of the management of differentiated thyroid cancers after surgery, where careful evaluation of the risk of cancer recurrence in the individual patient aids a balancing of the need to suppress TSH sufficiently with the need to avoid over treatment.
References
Filetti S, Durante C, Hartl D, et al. Thyroid cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:1856–83.
Jarząb B, Dedecjus M, Słowińska-Klencka D, et al. Guidelines of Polish National Societies diagnostics and treatment of thyroid carcinoma. 2018 update. Endokrynol Pol. 2018;69:34–74.
Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1–133.
Giovanella L, Duntas LH. Management of endocrine disease: the role of rhTSH in the management of differentiated thyroid cancer: pros and cons. Eur J Endocrinol. 2019;181:R133–45.
Francis GL, Waguespack SG, Bauer AJ, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015;25:716–59.
Fugazzola L, Elisei R, Fuhrer D, et al. 2019 European Thyroid Association guidelines for the treatment and follow-up of advanced radioiodine-refractory thyroid cancer. Eur Thyroid J. 2019;8:227–45.
Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610.
McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F, Sarlis NJ. Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med. 2002;34:554–64.
Grani G, Ramundo V, Verrienti A, Sponziello M, Durante C. Thyroid hormone therapy in differentiated thyroid cancer. Endocrine. 2019;66:43–50.
Biondi B, Cooper DS. Thyroid hormone suppression therapy. Endocrinol Metab Clin N Am. 2019;48:227–37.
Lamartina L, Montesano T, Falcone R, et al. Is it worth suppressing TSH in low- and intermediate-risk papillary thyroid cancer patients before the first disease assessment? Endocr Pract. 2019;25:165–9.
Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid. 2010;20:135–46.
Biondi B, Filetti S, Schlumberger M. Thyroid-hormone therapy and thyroid cancer: a reassessment. Nat Clin Pract Endocrinol Metab. 2005;1:32–40.
Rinaldi S, Plummer M, Biessy C, et al. Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: the EPIC study. J Natl Cancer Inst. 2014;106:dju097.
Giovanella L, Castellana M, Trimboli P. Unstimulated high-sensitive thyroglobulin is a powerful prognostic predictor in patients with thyroid cancer. Clin Chem Lab Med. 2019;58:130–7.
Biondi B, Bartalena L, Cooper DS, Hegedüs L, Laurberg P, Kahaly GJ. The 2015 European Thyroid Association guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism. Eur Thyroid J. 2015;4:149–63.
Suh B, Shin DW, Park Y, et al. Increased cardiovascular risk in thyroid cancer patients taking levothyroxine: a nationwide cohort study in Korea. Eur J Endocrinol. 2019;180:11–20.
Hong KS, Son JW, Ryu OH, Choi MG, Hong JY, Lee SJ. Cardiac effects of thyrotropin oversuppression with levothyroxine in young women with differentiated thyroid cancer. Int J Endocrinol. 2016;2016:9846790.
Gamper EM, Wintner LM, Rodrigues M, et al. Persistent quality of life impairments in differentiated thyroid cancer patients: results from a monitoring programme. Eur J Nucl Med Mol Imaging. 2015;42:1179–88.
Larisch R, Midgley JEM, Dietrich JW, Hoermann R. Symptomatic relief is related to serum free triiodothyronine concentrations during follow-up in levothyroxine-treated patients with differentiated thyroid cancer. Exp Clin Endocrinol Diabetes. 2018;126:546–52.
To J, Goldberg AS, Jones J, et al. A systematic review of randomized controlled trials for management of persistent post-treatment fatigue in thyroid cancer survivors. Thyroid. 2015;25:198–210.
Massolt ET, van der Windt M, Korevaar TI, et al. Thyroid hormone and its metabolites in relation to quality of life in patients treated for differentiated thyroid cancer. Clin Endocrinol (Oxf). 2016;85:781–8.
Vigário Pdos S, Chachamovitz DS, Teixeira Pde F, Rocque Mde L, Santos ML, Vaisman M. Exercise is associated with better quality of life in patients on TSH-suppressive therapy with levothyroxine for differentiated thyroid carcinoma. Arq Bras Endocrinol Metabol. 2014;58:274–81.
Schmidt ME, Wiskemann J, Johnson T, Habermann N, Schneeweiss A, Steindorf K. L-Thyroxine intake as a potential risk factor for the development of fatigue in breast cancer patients undergoing chemotherapy. Support Care Cancer. 2018;26:2561–9.
Moeller LC, Führer D. Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocr Relat Cancer. 2013;20:R19–29.
Haymart MR, Repplinger DJ, Leverson GE, et al. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. J Clin Endocrinol Metab. 2008;93:809–14.
He LZ, Zeng TS, Pu L, Pan SX, Xia WF, Chen LL. Thyroid hormones, autoantibodies, ultrasonography, and clinical parameters for predicting thyroid cancer. Int J Endocrinol. 2016;2016:8215834.
Huang H, Rusiecki J, Zhao N, et al. Thyroid-stimulating hormone, thyroid hormones, and risk of papillary thyroid cancer: a nested case-control study. Cancer Epidemiol Biomark Prev. 2017;26:1209–18.
Hu MJ, Zhang C, Liang L, et al. Fasting serum glucose, thyroid-stimulating hormone, and thyroid hormones and risk of papillary thyroid cancer: a case-control study. Head Neck. 2019;41:2277–84.
Kuijpens JL, Nyklíctek I, Louwman MW, Weetman TA, Pop VJ, Coebergh JW. Hypothyroidism might be related to breast cancer in post-menopausal women. Thyroid. 2005;15:1253–9.
Brandt J, Borgquist S, Manjer J. Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to risk of different breast cancer subgroups: a Malmö Diet and Cancer Study. Cancer Causes Control. 2015;26:1093–104.
Tosovic A, Becker C, Bondeson AG, et al. Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to breast cancer risk. Int J Cancer. 2012;131:2126–33.
Kim EY, Chang Y, Lee KH, et al. Serum concentration of thyroid hormones in abnormal and euthyroid ranges and breast cancer risk: a cohort study. Int J Cancer. 2019;145:3257–66.
Ortega-Olvera C, Ulloa-Aguirre A, Ángeles-Llerenas A, et al. Thyroid hormones and breast cancer association according to menopausal status and body mass index. Breast Cancer Res. 2018;20:94.
Chan YX, Knuiman MW, Divitini ML, Brown SJ, Walsh J, Yeap BB. Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer. Eur J Endocrinol. 2017;177:297–308.
Shi XZ, Jin X, Xu P, Shen HM. Relationship between breast cancer and levels of serum thyroid hormones and antibodies: a meta-analysis. Asian Pac J Cancer Prev. 2014;15:6643–7.
Jiskra J, Límanová Z, Barkmanová J, Smutek D, Friedmannová Z. Autoimmune thyroid diseases in women with breast cancer and colorectal cancer. Physiol Res. 2004;53:693–702.
Wu CC, Yu YY, Yang HC, et al. Levothyroxine use and the risk of breast cancer: a nation-wide population-based case-control study. Arch Gynecol Obstet. 2018;298:389–96.
Mondul AM, Weinstein SJ, Bosworth T, Remaley AT, Virtamo J, Albanes D. Circulating thyroxine, thyroid-stimulating hormone, and hypothyroid status and the risk of prostate cancer. PLoS One. 2012;7:e47730.
Puhr HC, Wolf P, Berghoff AS, Schoppmann SF, Preusser M, Ilhan-Mutlu A. Elevated free thyroxine levels are associated with poorer overall survival in patients with gastroesophageal cancer: a retrospective single center analysis. Horm Cancer. 2020;11:42–51.
Boursi B, Haynes K, Mamtani R, Yang YX. Thyroid dysfunction, thyroid hormone replacement and colorectal cancer risk. J Natl Cancer Inst. 2015;107:djv084.
Pinter M, Haupt L, Hucke F, et al. The impact of thyroid hormones on patients with hepatocellular carcinoma. PLoS One. 2017;12:e0181878.
Sarosiek K, Gandhi AV, Saxena S, et al. Hypothyroidism in pancreatic cancer: role of exogenous thyroid hormone in tumor invasion-preliminary observations. J Thyroid Res. 2016;2016:2454989.
Uzair ID, Conte Grand J, Flamini MI, Sanchez AM. Molecular actions of thyroid hormone on breast cancer cell migration and invasion via cortactin/N-WASP. Front Endocrinol (Lausanne). 2019;10:139.
Hsieh MT, Wang LM, Changou CA, et al. Crosstalk between integrin αvβ3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells. Oncotarget. 2017;8(15):24237–49.
Shinderman-Maman E, Cohen K, Weingarten C, et al. The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation. Oncogene. 2016;35:1977–87.
Davis PJ, Mousa SA, Schechter GP, Lin HY. Platelet ATP, thyroid hormone receptor on integrin αvβ3 and cancer metastasis. Horm Cancer. 2020;11:13–6.
Weingarten C, Jenudi Y, Tshuva RY, et al. The interplay between epithelial-mesenchymal transition (EMT) and the thyroid hormones-αvβ3 axis in ovarian cancer. Horm Cancer. 2018;9:22–32.
Schmohl KA, Mueller AM, Dohmann M, et al. Integrin αvβ3-mediated effects of thyroid hormones on mesenchymal stem cells in tumor angiogenesis. Thyroid. 2019;29:1843–57.
Chin YT, Wei PL, Ho Y, et al. Thyroxine inhibits resveratrol-caused apoptosis by PD-L1 in ovarian cancer cells. Endocr Relat Cancer. 2018;25:533–45.
Lin HY, Chin YT, Yang YC, et al. Thyroid hormone, cancer, and apoptosis. Compr Physiol. 2016;6:1221–37.
Meng R, Tang HY, Westfall J, et al. Crosstalk between integrin αvβ3 and estrogen receptor-α is involved in thyroid hormone-induced proliferation in human lung carcinoma cells. PLoS One. 2011;6:e27547.
Cicatiello AG, Ambrosio R, Dentice M. Thyroid hormone promotes differentiation of colon cancer stem cells. Mol Cell Endocrinol. 2017;459:84–9.
Catalano V, Dentice M, Ambrosio R, et al. Activated thyroid hormone promotes differentiation and chemotherapeutic sensitization of colorectal cancer stem cells by regulating Wnt and BMP4 signaling. Cancer Res. 2016;76:1237–44.
Wang T, Xia L, Ma S, et al. Hepatocellular carcinoma: thyroid hormone promotes tumorigenicity through inducing cancer stem-like cell self-renewal. Sci Rep. 2016;6:25183.
Kotolloshi R, Mirzakhani K, Ahlburg J, Kraft F, Pungsrinont T, Baniahmad A. Thyroid hormone induces cellular senescence in prostate cancer cells through induction of DEC1. J Steroid Biochem Mol Biol. 2020;201:105689.
Heublein S, Mayr D, Meindl A, et al. Thyroid hormone receptors predict prognosis in BRCA1 associated breast cancer in opposing ways. PLoS One. 2015;10:e0127072.
Jerzak KJ, Cockburn J, Pond GR, et al. Thyroid hormone receptor α in breast cancer: prognostic and therapeutic implications. Breast Cancer Res Treat. 2015;149:293–301.
Ditsch N, Toth B, Himsl I, et al. Thyroid hormone receptor (TR)alpha and TRbeta expression in breast cancer. Histol Histopathol. 2013;28:227–37.
Kim WG, Zhu X, Kim DW, Zhang L, Kebebew E, Cheng SY. Reactivation of the silenced thyroid hormone receptor β gene expression delays thyroid tumor progression. Endocrinology. 2013;154:25–35.
Bolf EL, Gillis NE, Barnum MS, et al. The thyroid hormone receptor-RUNX2 Axis: a novel tumor suppressive pathway in breast cancer. Horm Cancer. 2020;11:34–41.
Carr FE, Tai PW, Barnum MS, et al. Thyroid hormone receptor-β (TRβ) mediates runt-related transcription factor 2 (Runx2) expression in thyroid cancer cells: a novel signaling pathway in thyroid cancer. Endocrinology. 2016;157:3278–92.
Shao W, Kuhn C, Mayr D, et al. Cytoplasmic and nuclear forms of thyroid hormone receptor β1 are inversely associated with survival in primary breast cancer. Int J Mol Sci. 2020;21:330.
Kowalik MA, Puliga E, Cabras L, et al. Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming. J Hepatol. 2020;72:1159–69.
Wu SM, Cheng WL, Liao CJ, et al. Negative modulation of the epigenetic regulator, UHRF1, by thyroid hormone receptors suppresses liver cancer cell growth. Int J Cancer. 2015;137:37–49.
Wojcicka A, Piekielko-Witkowska A, Kedzierska H, et al. Epigenetic regulation of thyroid hormone receptor beta in renal cancer. PLoS One. 2014;9:e97624.
Ichijo S, Furuya F, Shimura H, et al. Activation of the RhoB signaling pathway by thyroid hormone receptor β in thyroid cancer cells. PLoS One. 2014;9:e116252.
Davis PJ, Lin HY, Hercbergs AA, Keating KA, Mousa SA. How thyroid hormone works depends upon cell type, receptor type, and hormone analogue: implications in cancer growth. Discov Med. 2019;27:111–7.
Mousa SA, Glinsky GV, Lin HY, et al. Contributions of thyroid hormone to cancer metastasis. Biomedicine. 2018;6:89.
Krashin E, Piekiełko-Witkowska A, Ellis M, Ashur-Fabian O. Thyroid hormones and cancer: a comprehensive review of preclinical and clinical studies. Front Endocrinol (Lausanne). 2019;10:59.
Gu G, Gelsomino L, Covington KR, et al. Targeting thyroid hormone receptor beta in triple-negative breast cancer. Breast Cancer Res Treat. 2015;150:535–45.
Shinderman-Maman E, Cohen K, Moskovich D, et al. Thyroid hormones derivatives reduce proliferation and induce cell death and DNA damage in ovarian cancer. Sci Rep. 2017;7:16475.
Leith JT, Mousa SA, Hercbergs A, Lin HY, Davis PJ. Radioresistance of cancer cells, integrin αvβ3 and thyroid hormone. Oncotarget. 2018;9:37069–75.
Goemann IM, Marczyk VR, Romitti M, Wajner SM, Maia AL. Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias. Endocr Relat Cancer. 2018;25:R625–45.
Casula S, Bianco AC. Thyroid hormone deiodinases and cancer. Front Endocrinol (Lausanne). 2012;3:74.
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Bednarczuk, T. (2021). Levothyroxine and Cancer. In: Kahaly, G.J. (eds) 70 Years of Levothyroxine. Springer, Cham. https://doi.org/10.1007/978-3-030-63277-9_9
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