Signal Pathway of Estrogen and Estrogen Receptor in the Development of Thyroid Cancer

Abstract

The molecular mechanisms underlying the development of thyroid cancer (TC) have been examined through extensive experiments. A large number of studies have shown that the incidences of thyroid cancer in women is much higher than that in men, so estrogen plays a key role in the development of thyroid cancer. Estrogen plays its growth-promoting role through classical genomic and non-genomic pathways mediated by membrane-bound estrogen receptors. It also can affect tumor progression by regulating the tumor microenvironment. We summarize the understanding of molecular mechanisms of estrogen signaling pathways in thyroid cancer. Furthermore, it will provide a new target for the treatment of thyroid carcinoma by blocking estrogen and its related action pathway.

Keywords: estrogen; estrogen receptor; signal pathway; thyroid cancer; thyroid cancer cells.

Figure 1

Estrogen and estrogen receptor-mediated pathways in thyroid cancer. (a) PI3K/AKT/mTOR pathway: activation of PI3K promotes cell proliferation and differentiation. PTEN gene can prevent PI3K phosphorylation and promote apoptosis, while activation of Bcl-2 gene promotes cell proliferation; AKT can promote NF-κB nuclear translocation, activate target genes, and promote cell survival. (b) Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway: E2 can make mitogen-activated protein (MAP) kinase isoenzymes and ERK 1/2 strongly phosphorylated, and then promote the expression changes of apoptosis-related factors, such as Bcl-2, Bax, and cyclinD1, increasing the ability of cell proliferation and survival. ERα can interact directly with IQGAP1 to phosphorylate ERK1/2 thereby promoting cell proliferation. (c) Reactive oxygen species (ROS)-related pathways: E2 can stimulate ROS production by acting on NOX4 that may be located in the plasma membrane, endoplasmic reticulum, nuclear membrane, and mitochondria, and then ROS induces the overexpression of HIF-1α. (d) E2 increases cyclin D1 protein expression and reduces the expression of p27 and β-catenin by ERα. Overexpression of ERα or ERβ decreased the activity of PPARγ protein, thereby significantly promoting the proliferation and migration of thyroid cancer cells. TRIM16 has “anti-estrogen” activity, and its anti-estrogen action is mainly concentrated in ERβ.