I found an interesting review article about how sex hormones might be linked to the development of thyroid cancer. The article is composed of old and recent studies of this hypothesis.The researchers investigated the expression of estrogen receptors α and β on normal and abnormal thyroid tissue and composed tables to determine if estrogen is a contributing factor in tumorigenesis.
Thyroid diseases are more common in women than men, especially during puberty and menopause. Also, women are three times more likely than men in acquiring thyroid cancer, indicating that a sex hormone like estrogen, might be a contributing factor of getting thyroid cancer. Estrogen is a key factor in thyroid regulation. The hormone increases the thyroxine-bind-globulin, which is responsible for transporting the thyroid hormones in the blood stream, and is used for women with hypothyroidism. The researchers studied the effects of estrogen on thyroid function, growth, and regulation.
Estrogen has two receptors, ERα and ERβ. After ERα and ERβ bind to estrogen (or Estradiol E2), the receptor dimerizes and becomes activated. It can now initiate estrogen response elements to encode specific genes. Also, when ERα and ERβ are activated, it can also signal to other transcription factors that can encode other genes. Estrogen receptors have been present in both normal and abnormal human thyroid cells. Also when estrogen binds to ERα it promotes cell proliferation and cell growth. When estrogen binds to ERβ, it signals apoptosis. The expression of ERα and ERβ were noticed in medullary thyroid cancer, which suggest a promising factor in tumorigenesis. There were studies that investigated the ERα and ERβ in normal and abnormal tissue. Table 2. shows that ERα and ERβ were prevalent in medullary thyroid carcinoma, and a few studies indicated no expression of ERα in medullary thyroid carcinoma.
Studies In Vitro
There were a few studies that illustrated proliferation by estrogen. Table 3. Illustrates in some cases ERα is being expressed, which increases cell proliferation of the thyroid cancer cells.
|Estrogen receptor (ER) +: presence of expression, –: absence of expression; NPA87, KAT5, and BCPAP: human papillary thyroid carcinoma cell lines; WRO and FRO: human follicular thyroid carcinoma cell lines; Nthy-3-1: human normal transformed thyroid cell line; ARO: human anaplastic thyroid carcinoma cell line; HTC-TSHr: human thyroid carcinoma cell line lacking endogenous TSH receptor; XTC-133: thyroid cancer cell line of Hurthle cell origin; FRTL-5: Fischer rat thyroid cell line. Mng: multinodular goiter; Ca: carcinoma; Ade: adenoma; N: normal thyroid; TT: human medullary thyroid carcinoma cell line; ↑: increase, ↓: decrease, and 0: no effect, after E2 exposure. *: thyroid tissue obtained in surgical resection, under organotypic culture conditions for 48 hours; **: suspension cultures of thyroid follicles.|
Signal pathways can also activate the proliferation of thyroid cells by estrogen. Estrogen can signal the initiation of PI3K, which is an enzyme that is involved in cell growth, survival, differentiation, and metabolism. Also, estrogen can activate Erk1/2, which is involved in mitosis. When Erk1/2 and PI3K are activated, it can prevent apoptosis and stimulate cell cycle progression. It is noticed that estrogen increases the expression of cyclin D1 in thyroid cancer. Since estrogen upregulates cyclin D1 and cyclin A1, it illustrates that estrogen partakes in tumorigenesis in thyroid cancer. Estrogen also upregulates the proto-oncogene, c-fos, which encodes for cell proliferation and cell transformation, which illustrates that estrogen plays a role in tumor progression.
There is indication that estrogen may contribute in human thyroid cells by regulation proliferation and thyroid function. The ERα and ERβ expression plays a key role in thyroid cancer cell proliferation and the development of a cancerous tumor. Further studies must be accomplish to really understand the mechanisms of estrogen in the thyroid gland to develop targeted therapies.
1. Link to class
In class we have learned that cyclin D1 is controlled by the extracellular signals by mitogenic factors (for example a hormone), and it responsible in controlling the cell cycle. If estrogen is increasing the expression of cyclin D1, then the cell cycle is going to be upregulated and consequently lose control of cell growth and division leading to the formation of a tumor. In addition, estrogen can activate Erk1/2 and PI3K pathways which can prevent apoptosis. This is a hallmark of caner, resisting cell death. Since these pathways prevent cell death, it is very beneficial to the carcinoma, because apoptosis is no longer an anticancer therapy and can no longer signal cell death for rapidly growing cells.
Table 3 shows that some studies have observed proliferation of thyroid cells by estrogen and concluded that E2 does increase cell growth in thyroid cells. However, I was confused on how the expression of both ERα and ERβ will activate proliferation of cells, since ERα signals cell growth and ERβ signals cell death. I denoted this observation with a circle and also denoted the accurate ERα and ERβ expression with arrows. The data with the arrows are telling me that since there is expression of ERα, it will signal proliferation, and when there is high expression of ERβ, it will signal apoptosis, therefore proliferation will decrease. However, I do not understand how both the expression of ERα and ERβ will signal proliferation. Perhaps estrogen is upregulating ERα more than ERβ, therefore the cell is inducing proliferation. I need to investigate and research more on the ERα and ERβ expression and it's effect on thyroid cells.
3. Therapeutic Targets
The researchers concluded that one must investigate more on the mechanism of ERα and ERβ and its functions to possibly develop a targeted hormone therapy. Since, cancer is so dynamic, adaptive, and multi-dimensional, it is very difficult to cure cancer. If one does develop a therapeutic target to inhibit estrogen, it must be selective, effective, and potent in order to cure thyroid cancer. This is because, targeted therapies are known to become ineffective. If a patient is treated with a targeted therapy and later has a relapse and is then treated with the same therapy, most likely that patient will be resistant to that treatment. I believe if one is going to develop a targeted hormone therapy one must understand the multi-dimensional component of cancer and target the ecosystem of the cancer.
Overall, I thought this article was very interesting because it gathered old and recent studies on how the sex hormone, estrogen, can contribute to the development of thyroid cancer. Also, I was wondering if there were any inhibitors for ERβ, if so that can contribute to the proliferation of the cell which will lead to tumorigenesis. Also, the article did not mention of the possibility of the absence of ERβ and its possible consequences to the cell. I would be interesting to find out the consequences of ERβ being absent in the cell.
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