Journal of Thyroid Disorders & Therapy
Open Access

T4 can Influence Breast Carcinogenesis by Primarily Increasing its Semi Transcription Factor

Cheean Ly^{* *}Correspondence: Cheean Ly, Department of Biomedical Sciences, Yonsei University, Seoul, South Korea, Email:

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About the Study

While hypothyroidism is a risk factor for breast cancer, long-term exposure to overdoses of thyroid replacement medication with Thyroxine (T4) may enhance the risk. The goal of this study is to look at the impact of T4 on the proliferation and apoptosis of mammary tumours in hypo- and euthyroid rats, as well as the probable processes involved [1].

Techniques and materials: Female Sprague-Dawley rats were given a single dose of dimethylbenzathracene (15 mg/rat) at 55 days of age and were divided into three groups: Hypothyroidism (HypoT; 0.01% 6-N-propyl-2-thiouracil -PTU in drinking water, n=20), hypothyroidism treated with T4 (HypoT+T4; 0.01% PTU in drinking water [2,3]. Tumor explants from HypoT and EUT rats were obtained at sacrifice and treated for 15 minutes with 1010 M T4 in DMEM/F12 without phenol red with 1% Charcoalized Fetal Bovine Serum or DMEM/F12 only for 24 hours to evaluate changes in the expression of hormone receptors and proteins related to apoptosis and proliferation by immunohistochemistry and Western Blot. 

Hypothyroidism slows mammary carcinogenesis in vivo, but T4 therapy reverses the protective benefits. T4's proliferative and anti-apoptotic actions differed in vitro depending on thyroid state. The key signalling mechanism implicated in EUT tumours was cross-talk with other receptors such as ER, PgR, and HER2.

Although v3 integrin, PI3K/AKT and ERK signalling pathways were active in HypoT cancers, the non-genomic signalling pathway of T4 was the main mechanism implicated. T4 can control mammary carcinogenesis by primarily activating its nongenomic signalling route and interacting with other hormone or growth factor pathways, implying that T4 overdoses can raise the risk of breast cancer. In the general population, breast cancer and thyroid problems such as hypothyroidism and hyperthyroidism are quite common. The possibility of a connection between them has been argued for decades and remains contentious. On the one hand, it is well recognized that hypothyroidism is a cancerpreventive factor, as evidenced by epidemiological and retrospective analyses. Breast cancer is less common in those who have hypothroidism. In a prior work, we discovered that hypothyroidism delayed tumour emergence, lowered tumor incidence, and slowed tumor progression in rats. Clinical hypothyroidism was found to be a powerful protective factor against breast cancer in people, lowering tumour incidence and aggressiveness. When compared to euthyroid women, women with primary hypothyroidism had a 61% lower incidence of invasive breast cancer and were more likely to have localized disease and no lymph node involvement. Also, hypothyroid individuals who got breast cancer had a more indolent illness with smaller tumors.

Hyperthyroidism, on the other hand, is linked to an increased incidence and aggressiveness of breast cancer. In vitro and in vivo triiodo-L-thyronine (T3) and L-thyroxine (T4) are proliferation factors for various human cancer cell lines, according to xenograft experiments. Thyroid hormones function via genetic and/or non-genomic signalling mechanisms. Thyroid hormones' genomic activities are mediated by nuclear Thyroid hormone Receptors (TR), which regulate gene expression. They can, however, bind receptor molecules with little structural resemblance to TRs, such as the cell surface receptor site on v3 integrin, and activate non-genomic effects, regulating cell proliferation and angiogenesis further. Levothyroxine, a synthetic version of T4, is a regularly prescribed thyroid medicine used to treat hypothyroidism and goitre. Therapy dose should be determined by age, patient weight, BMI, pregnant status, and other factors. Yet, research suggests that 40-48% of patients getting Levothyroxine are given an overdose [4].

Inadequate T4 intake not only causes hyperthyroidism and thyrotoxicosis, but it also increases the risk of cardiovascular, bone, and cancer issues. A recent study found that using Levothyroxine raised the risk of breast cancer by 45% in women over the age of 65% and 19% in those under the age of another study found that using thyroid supplements for non-disease reasons (mainly weight reduction and reproductive issues) was linked to a small increase in breast cancer risk [5].

Given that hypothyroidism might delay cancer development and thyroid hormones have been linked to breast tissue growth and eventual malignancy, we anticipated that long-term usage and overdoses of thyroid replacement treatment with T4 to treat hypothyroidism were linked to an increased risk of breast cancer.

To verify this idea, we investigated the effects of T4 on the proliferation and apoptosis of mammary tumors from hypo and euthyroid rats, as well as the putative processes involved. 

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References

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