Thyroxine (T4) and Cancer

Under development – please ignore until it has been reviewed and this notice removed.

Introduction

Hypothyroidism has been “known” to be protective against cancer for many decades with suspected links between the thyroid and cancer going back over a century. This topic looks at recent research that reveals how T4 but not T3 promotes cancer by binding to the integrin αvβ3 receptor. T4 refers to all forms of thyroxine from the thyroid or from tablets.

IMPORTANT: If you have cancer or are worried about it you should seek advice from your doctor or an oncologist. I have no cancer expertise whatsoever. The objective is to draw attention to the carcinogenic effects of T4 and change thyroid treatment so that cancer deaths are reduced.

While studying the effects of thyroxine on cancer we should keep in mind three questions: –

  1. How and to what degree does thyroxine promote cancer?
  2. How much illness and death does it lead to?
  3. How confident can we be with the data, what degree of certainty is there?

We will see how T4 acting on the integrin αvβ3 receptor promotes cancer by the following mechanisms: –

  1. T4 proliferates the growth and metastasis of cancer cells.
  2. T4 increases angiogenesis (formation of new blood vessels) – cancer cells need new blood vessels to grow.
  3. T4 inhibits apotosis – inhibits the death of cancer cells.
  4. T4 enhances radioresistance – protects cancer from radiotherapy.

These effects are dose dependent. Studies are generally presented in chronological order within each section, most studies are recent.

Some studies look at the potential to treat cancer by lowering serum T4, or by blocking the ability of T4 to bind to integrin αvβ3 receptors. This provides good evidence. This topic does not discuss or advise on cancer treatment. This should be done by the oncologist in charge of the patient’s care.

Cancers can have profound effects on thyroid hormones so we will only look at prospective studies. That is studies that measure thyroid hormone levels and observe cancer incidence several years later. These studies have limitations, the most obvious being that they look at hormone levels at a snapshot in time. This is likely to dilute the results if the subjects who had abnormal hormone levels are given corrective treatment. There is also the possibility that abnormalaties might worsen and remain untreated.

There are many ways thyroid hormones can affect cancer risk so before we look at the integrin αvβ3 receptor we consider two notable exceptions: liver cancer and breast cancer.


Liver Cancer and Thyroid Hormone

Liver cancer is a bit unusual in that it seems that thyroid hormone is protective, there could be various reasons including associations between hypothyroidism and obesity, insulin resistance and hyperlipidemia. Liver cancer accounts for about 3% of UK cancer deaths. If you are interested in more detail here is a study Abnormal and Euthyroid Ranges of Thyroid Hormones in Serum and Liver Cancer Mortality: A Cohort Study Won Sohn, Yoosoo Chang, Yong Kyun Cho, Yejin Kim, Hocheol Shin and Seungho Ryu Cancer Epidemiol Biomarkers Prev October 1 2020 29 (10) 2002-2009


Breast Cancer and Thyroid Hormone

This section presents evidence that higher levels of thyroid hormone (both T3 and T4) stimulate breast cancer, perhaps because thyroid hormone has oestrogenic effects. It is not intented to review breast cancer and thyroid hormone in detail, just show that breast cancer is a special case which confounds our discussion of the integrin αvβ3 receptor and thyroxine. It may be that the effects of T3 on breast cancer are greater than the benefit it gives in lowering T4 levels. Thus, when studying the effects of T4 on the Integrin αvβ3 receptor we should treat breast cancer as an exception. Breast cancer accounts for about 7% of all UK cancer deaths. The studies are presented in chronological order.


Tosovic, A., Bondeson, AG., Bondeson, L. et al. Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res 12, R33 (2010). https://doi.org/10.1186/bcr2587

This study measured TSH and T3 (not T4) and followed up breast cancer cases that occurred at least three years later thus avoiding the effects of cancer on TFTs. The study found a strong dose-response relation between T3 and breast cancer in post-menopausal women (see Table 3). No association with TSH was found and T4 was not measured. Only people who had an abnormal TSH, a history of thyroid disease or an enlarged thyroid were included in the study.


Tosovic, A., Becker, C., Bondeson, A.-G., Bondeson, L., Ericsson, U.-B., Malm, J. and Manjer, J. (2012), Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to breast cancer risk. Int. J. Cancer, 131: 2126-2133. https://doi.org/10.1002/ijc.27470

This study used stored blood samples to compare TSH, fT3, fT4 in breast cancer patients and controls. So, unlike the previous study it wasn’t limited to those with abnormal thyroids. There was no association between fT3 and breast cancer whereas breast cancer was strongly associated with fT4.


Tosovic A, Bondeson AG, Bondeson L, Ericsson UB, Manjer J. Triiodothyronine levels in relation to mortality from breast cancer and all causes: a population-based prospective cohort study. Eur J Endocrinol. 2013;168:483–90. https://doi.org/10.1530/EJE-12-0564.

This is a follow-up to the first study with a similar cohort. This study looks at breast cancer mortality as opposed to cases. It finds that pre-diagnostic T3 levels are positively associated with the risk of breast cancer-specific death in post menopausal women (see Table 3). The hazard ratios were higher than in the previous study suggesting that T3 not only increases the risk of breast cancer but also makes it more deadly. There was no link between T3 and other forms of cancer.


Leese GP, Soto-Pedre E, Donnelly LA. Liothyronine use in a 17 year observational population-based study – the tears study. Clin Endocrinol. (2016) 85:918–25. doi: 10.1111/cen.13052

This is an observational study not a prospective one. (The full paper can be obtained via Sci-Hub). Table 3 shows a breast cancer hazard ratio (HR) of 1.754 for people who have ever taken liothyronine compared to levothyroxine only. Fig 1 shows similar or higher HRs according to the percentage of liothyronine prescriptions (vs levothyroxine) received. We don’t know whether the people receiving liothyronine were on higher overall thyroid hormone doses. There wasn’t a clear cut relationship between percent liothyronine prescriptions and HR which might suggest it is the hormone dose and not the form (L-T3 or L-T4) that is associated with breast cancer. This study is not good evidence for breast cancer and T3 but it is a large scale well known study, hence its inclusion.


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(12): 3257- 3266.

This is a large study over a relatively short period of just under five years on average. They measured free T3 and T4 whereas other studies tended to measure total T3 and T4. As can be seen in Tables 2 and 4 a high fT4 was associated with an increased risk of breast cancer and a high TSH with a lower risk. fT3 within the reference interval showed no association with breast cancer link but there was increased breast cancer risk for post-menopausal women with a high fT3.


Summary: Liver and Breast Cancer

From the integrin αvβ3 receptor perspective liver and breast cancers should be viewed as exceptions. Thyroid hormone appears to be protective against liver cancer and to promote breast cancer. These cancers account for about 10% of cancer deaths. We will look at how thyroxine acting on the integrin αvβ3 receptor increases overall cancer risk and mortality.


The Integrin αvβ3 Receptor and Thyroxine

The following diagram illustrates integrin αvβ3 receptors. In general thyroid hormone action is ‘genomic’, it works by T3 binding to nuclear receptors which (along with cofactors) bind to Thyroid Response Elements (TREs) on the DNA. T4 has little ability to bind nuclear receptors, it must be converted to T3 and so T4 is considered a prohormone.

There are other, non-genomic receptors such as the Integrin αvβ3 Receptor on the cell membrane. Integrin αvβ3 binds both T3 and T4 but T4 has the dominant action. So, T4 is the active hormone for the Integrin αvβ3 receptor.


Figure 2 from: Cayrol, F, Sterle, HA, Díaz Flaqué, MC, Barreiro Arcos, ML, Cremaschi, GA. Non-genomic actions of thyroid hormones regulate the growth and angiogenesis of T cell lymphomas. Front Endocrinol. 2019;10:63. doi: 10.3389/fendo.2019.00063


Tetrac (tetraiodothyroacetic acid)

A number of studies mention Tetrac, so it is useful at this stage to know a little about it. Tetrac (tetraiodothyroacetic acid) is a deaminated analogue of L-thyroxine, as can be seen in the diagram below. Tetrac (e) is very similar to thyroxine (a). Tetrac blocks the binding of T4 to the Integrin αvβ3 Receptor and is used in experiments as a potentioal cancer treatment. This is all we need to know about Tetrac, it stops T4 binding to the Integrin αvβ3 Receptor.

R. G., Ahmed & Davis, Paul & Davis, Faith & Vito, Paolo & Farias, Ricardo & Luly, Paolo & Pedersen, Jens & Incerpi, Sandra. (2013). Nongenomic Actions of Thyroid Hormones: From Basic Research to Clinical Applications. An Update. Immunology Endocrine & Metabolic Agents – Medicinal Chemistry (Formerly Current Medicinal Chemistry – Immunology Endocrine & Metabolic Agents). 13. 46-59. 10.2174/1871522211313010005.

T4 binding to the integrin αvβ3 receptor increases cancer risk and mortality. The studies are in chronological order so we can see how the science has advanced in the last few years.

Cancerous Actions of Integrin αvβ3 Receptor

Davis, P.J.; Davis, F.B.; Mousa, S.A.; Luidens, M.K.; Lin, H.Y. Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu. Rev. Pharmacol. Toxicol. 2011, 51, 99–115. https://doi.org/10.1146/annurev-pharmtox-010510-100512

This review summarises the state of knowledge as of 2011. T4 is biologically active at the intergrin receptor. The S2 pathway binds T4 and, to a lesser extent, T3 which results in cancer cell proliferation. The integrin αvβ3 receptor is widely expressed in cancer cells.

As stated earlier tetrac blocks the binding of T4 to the integrin receptor. The review describes a study in which human cancer cells were grafted into mice. “Tetrac and nanoparticulate tetrac (the latter at one-tenth the dose of unmodified tetrac) strongly inhibited the growth of human renal carcinoma cells (33), medullary carcinoma of the thyroid (34), follicular thyroid cancer cells (35), chemoresistant breast cancer cells (30, 36), and pancreatic cancer cells (37).

The review also describes how tetrac can sensitize tumour cells to radiotherapy by inhibiting integrin αvβ3 receptor binding. “Integrin αvβ3 has been reported to modulate cancer cell responses to radiation (43). Hercbergs et al. (44) have recently shown that mouse glioma cells exposed briefly to micromolar concentrations of tetrac in vitro exhibit up to a threefold increase in radiosensitivity.


Hercbergs A, Johnson RE, Ashur-Fabian O, Garfield DH, Davis PJ. Medically Induced Euthyroid Hypothyroxinemia may Extend Survival in Compassionate Need Cancer Patients: An Observational Study. Oncologist (2015) 20(1):72–6. doi: 10.1634/theoncologist.2014-0308

We have seen how the integrin αvβ3 receptor has a cruical role in cancer progression. We now show evidence that T4 activates this mechanism.

This study looked at 23 patients with end stage cancer. They were given methimazole to suppress the thyroid and liothyroine to restore clinical euthyroidism. i.e. their T4 was replaced with T3. The study was not placebo controlled but gave striking results both in terms of survival and radiologic improvement but we should not underestimate the power of the mind in such extreme cricumstances. There follows quotations from the intorduction to the study that illustrate the benefit of reducing T4 levels. ‘hypothyroxiniemia’ refers to low T4 levels.

In a phase II clinical trial of recurrent glioblastoma multiforme (GBM) conducted by the author (A.H.), medically induced hypothyroidism was associated with significantly longer progression-free survival and overall survival rates [5, 6]. In that study, it was found that prolongation of survival correlated significantly and independently with circulating free thyroxine (FT4) levels

The integrin is amply expressed by cancer cells and rapidly dividing endothelial cells and is not well expressed by or activated in quiescent, nonmalignant cells [3]

Within the cell, T4 serves as a prohormone for T3, and T3 is the metabolically and genomically important form of thyroid hormone [1]. At the integrin, in contrast, the thyroid hormone receptor affinity for T4 is higher than that for T3 [7], and T4 is a more potent inducer of tumor cell proliferation than is T3 [9]

Addition of T3 rapidly reduced serum thyrotropin (TSH) and FT4 levels and was associated with rapid clinical and radiologic improvement [11]

Comments from the Results and Discussion of the study: –

The odds of surviving at least 12 months for 19 of 23 individual patients were estimated to be lower than 15%–20%, whereas 19 of 23 from the managed group (83%) survived more than 12 months and 12 of 23 (52%) survived more than 24 months versus an estimated 1 of 23 (4.4%).

Radiologically documented tumor regression was observed following exogenous l-T4 withdrawal alone (n = 3). These were unusually rapid and durable responses in association with chemotherapy and/or radiotherapy. Overall response rate (complete and partial [15]) was 100%, that is, there was complete response (CR) in 5 and partial response (PR) in 18.

In preclinical studies, T4 enhances cancer cell proliferation, migration, invasion, and angiogenesis [3, 10, 17], apparently acting via the thyroid hormone receptor on cell surface integrin αvβ3 [3, 4]. Supraphysiologic amounts of T3 are required at this receptor to stimulate tumor cell proliferation [3, 9]. The highly unusual instances of rapid tumor regression observed following exogenous l-T4 discontinuation in the case histories provided in this paper in a variety of solid tumors are unusual in non-sex-hormone-dependent tumors

Lin HY, Tang HY, Leinung M, Mousa SA, Hercbergs A, Davis PJ. Action of Reverse T3 on Cancer Cells. Endocr Res (2019) 44(4):148–52. doi: 10.1080/07435800.2019.1600536

This in-vitro study shows that both T4 and rT3 enhances the proliferation of glioblstoma cells (aggressive brain cancer cells), see graphs below. Note the effect is not additive, T4 and rT3 have similar level of effect by themselves or combined.

Lin HY, Tang HY, Leinung M, Mousa SA, Hercbergs A, Davis PJ. Action of reverse T3 on cancer cells. Endocr Res. 2019;44(4):148–152. doi:10.1080/07435800.2019.1600536.

For anyone who is interested the following review gives an extensive summary of the evidence so far: Hercbergs A. Clinical Implications and Impact of Discovery of the Thyroid Hormone Receptor on Integrin αvβ3-A Review. Front Endocrinol (Lausanne). 2019 Aug 23;10:565. doi: 10.3389/fendo.2019.00565. PMID: 31507530; PMCID: PMC6716053.https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6716053/ .


Cayrol, F, Sterle, HA, Díaz Flaqué, MC, Barreiro Arcos, ML, Cremaschi, GA. Non-genomic actions of thyroid hormones regulate the growth and angiogenesis of T cell lymphomas. Front Endocrinol. 2019;10:63. doi: 10.3389/fendo.2019.00063 . This review describes studies that reveal the role of T4 and the integrin αvβ3 receptor in cancer.

Integrin αvβ3 is a member of a large group of heterodimeric transmembrane receptors that regulate cell-cell and cell-extracellular matrix (ECM) interactions and enable cells to respond to their environment (10).‘ ‘Interestingly this integrin is highly expressed in proliferating cells, like malignant cancer cells‘ ‘It is well-known that the growth, invasiveness, and dissemination of a tumor are highly associated with angiogenesis.‘ ‘the role of integrin αvβ3 as the membrane receptor for THs and how its activation induces the proliferation and survival of different types of cancer cells‘ ‘In this review, we will focus on the role of integrin αvβ3 as the membrane receptor for THs and how its activation induces the proliferation and survival of different types of cancer cells.

Angiogenesis is the formation of new blood vessels from pre-existing ones. Even though it is a fundamental physiological event, in certain situations angiogenesis can also be negative; the formation of new blood vessels contributes to the progression of several pathologies and is crucial in tumor growth and metastasis. Consequently, angiogenesis is essential for the growth, spreading and infiltration of malignant cells within tissues (64).‘ ‘A number of in vitro and in vivo studies have supported a role for THs in the proliferation of tumor cells (75, 7779) and as proangiogenic factor in many types of cancer (15, 75, 76, 80)

At physiological free hormone concentrations T4 is maximally active at the S2 site on integrin αvβ3, however significantly higher than physiological levels of free T3 are required to induce proliferative activity via this receptor (5)

Summary: Cancerous Actions of Integrin αvβ3 Receptor

The above studies and reviews show how T4 acting at the integrin αvβ3 receptor at physiologic levels promotes and protects cancers. The evidence for this is strong and we can have a good degree of certainty in this ‘natural’ process.

We need to ask: Does current levothyroxine therapy affect cancer risk? Is levothyroxine therapy safe?