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Estrogen and Its Role in Thyroid Cancer

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Estrogen and Its Role in Thyroid Cancer M Derwahl and D Nicula Estrogen in thyroid cancer 21:5 T273–T283 Thematic Review Estrogen and its role in thyroid cancer Correspondence Michael Derwahl and Diana Nicula should be addressed to M Derwahl Department of Medicine, St Hedwig Hospital and Charite, University Medicine Berlin, Grosse Hamburger Straße Email 5-11, 10115 Berlin, Germany [email protected] or [email protected] Abstract Proliferative thyroid diseases are more prevalent in females than in males. Upon the onset of Key Words puberty, the incidence of thyroid cancer increases in females only and declines again after " thyroid menopause. Estrogen is a potent growth factor both for benign and malignant thyroid cells " estrogen that may explain the sex difference in the prevalence of thyroid nodules and thyroid cancer. " cell signaling It exerts its growth-promoting effect through a classical genomic and a non-genomic pathway, " growth factor receptor mediated via a membrane-bound estrogen receptor. This receptor is linked to the tyrosine " neoplasia kinase signaling pathways MAPK and PI3K. In papillary thyroid carcinomas, these pathways may be activated either by a chromosomal rearrangement of the tyrosine receptor kinase TRKA, by RET/PTC genes, or by a BRAF mutation and, in addition, in females they may be stimulated by high levels of estrogen. Furthermore, estrogen is involved in the regulation of angiogenesis and metastasis that are critical for the outcome of thyroid cancer. In contrast to other carcinomas, however, detailed knowledge on this regulation is still missing for thyroid cancer. Endocrine-Related Cancer Endocrine-Related Cancer (2014) 21, T273–T283 Introduction Both benign and malignant thyroid tumors are 3–4 times (Rossing et al. 2000, Sakoda & Horn-Ross 2002, Cornet more prevalent in females than in males (Dean & Gharib 2013). However, in a recent retrospective cohort study of 2008, Li et al. 2013). Whereas in prepubertal girls and boys 145 007 postmenopausal women, no association between (rare), thyroid cancer is roughly equally represented, with the risk of thyroid cancer and hormonal or reproductive the onset of puberty the incidence increases in females by factors such as age at menarche or menopause, parity, and up to 14 times (Farahati et al. 1997). After menopause, the bilateral oophorectomy was observed (Kabat et al. 2012). incidence decreases again (Li et al. 2013). Only women who had a first live birth between the age In several studies, pregnancy was associated with a of 20 and 24 years had an increased risk of papillary higher risk of thyroid cancer (Galanti et al. 1995, Rossing thyroid cancer (PTC; Kabat et al. 2012). et al. 2000, Sakoda & Horn-Ross 2002, Horn-Ross et al. Genetic factors do not seem to confer a higher risk 2011). In contrast, low dose of estrogen in contraceptives of thyroid cancer to females. In a case–control study of 344 and in replacement therapy in postmenopausal women PTCs and 452 controls, the association between PTC and does not contribute to a higher risk of thyroid cancer (Kabat 1151 tag single-nucleotide polymorphisms (SNPs) in 58 et al. 2012). Some studies even found an inverse association candidate gene regions involved in sex hormone synthesis between the use of contraceptives and the risk of thyroid and metabolism did not show a significant correlation cancer, which may be explained by the low concentrations between the investigated SNPs and the risk of PTC of 17b-estradiol (E2) in currently used contraceptives (Schonfeld et al. 2012). http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-14-0053 Printed in Great Britain This paper forms part of a special thematic review section on New Concepts and Challenges in Thyroid Cancer. The guestDownloaded editor forfrom this Bioscientifica.com section was Laura at 09/30/2021 Ward, 05:56:17AM Universidade Estadual de Campinas, Brazil. via free access Thematic Review M Derwahl and D Nicula Estrogen in thyroid cancer 21:5 T274 The strongest support for estrogen as a risk factor of In addition, a novel membrane-bound ER, referred differentiated thyroid cancer comes from experimental to as ERx, was detected in the brain and the uterus studies that have clearly demonstrated that E2, the main (Toran-Allerand et al. 2002). The existence of this receptor female sex hormone, is a potent stimulator of both human in the thyroid is still unknown. benign and malignant thyroid cells (Manole et al. 2001, et al et al et al Zeng . 2007, Chen . 2008, Kumar . 2010, ER expression in benign and et al Rajoria . 2010). Interestingly, E2 was equally potent malignant thyroid tissues in its growth-promoting effect on human thyroid cells derived from male and female thyroid glands, which First indirect evidence for the presence of ERs in benign underlines the relevance of the hormone rather than of and malignant thyroid tissues (Table 1) came from ligand other sex-specific factors (Manole et al. 2001). studies (Molteni et al. 1981). Later ER immunoreactivity In summary, epidemiological, clinical, and experi- was detected in normal thyroid tissue, thyroid adenomas, mental data are indicative of a role of estrogen in the goiters, and differentiated and undifferentiated thyroid pathogenesis of proliferative thyroid diseases. carcinomas (Diaz et al. 1991, Mizukami et al. 1991, Hiasa et al. 1993). However, widely varying and, in part, contradictory results were reported. Some authors did Estrogen and its receptors not find ERs by immunohistochemical staining in normal thyroid tissue and adenomas or goiters (Jaklic et al. 1995, Estrogens are steroid hormones that play a key role in Arain et al. 2003), while others detected ER staining in the regulation of not only growth, differentiation, and approximately 10% to more than 50% of benign thyroid function of the reproductive organs but also bone, lesions (Diaz et al. 1991, Mizukami et al. 1991, Hiasa et al. and the cardiovascular and immune systems in males 1993, Tavangar et al. 2007). and females (Heldring et al. 2007). Estrogens that are A similar picture emerged when comparing immu- effective in humans include estrone, estriol, and E2,of nostaining of thyroid cancer samples. Although ER which E2 has the highest affinity to the estrogen receptors immunostaining was described in less than 10% to over (ERs) and the highest potency (Kuiper et al. 1997). The 60% of the samples in the majority of investigations action of estrogen occurs via a classical genomic and a (Haruta et al. 1990, Diaz et al. 1991, Mizukami et al. 1991, non-genomic pathway. The genomic mode of action is Hiasa et al. 1993, Lewy-Trenda 1998, Tavangar et al. 2007), Endocrine-Related Cancer mediated through ERa and ERb, which are members of a no ER immunoreactivity was observed in other studies large family of nuclear transcription factors (Mangelsdorf (Jaklic et al. 1995, Arain et al. 2003). These widely varying et al. 1995). For activation, estrogen has to enter the cell results were described for both papillary carcinoma and where it binds to its receptors ERa and ERb, which is follicular thyroid carcinoma (FTC) samples. The discre- followed by a nuclear translocation, homo- or hetero- pancies may be explained by technical factors such as the dimerization of the estrogen–ER complex, and its binding use of different monoclonal or polyclonal antibodies or to an estrogen-responsive element (ERE) in the promoter various staining procedures. region of different target genes (Nilsson et al. 2001). For the However, using considerably more sensitive reverse transactivation of genes, a process of recruitment and transcription PCR, detection of ER mRNAs in malignant binding of different coactivators is mandatory. thyroid tissues also varied between less than 20% and up In contrast to the slow process of transactivation of to 100% of samples (Yane et al. 1994, Dalla Valle et al. target genes, the non-genomic action of estrogen, which 1998). Therefore, it is likely that these discrepancies may is mediated by a membrane-associated estrogen receptor be also due to epigenetic modifications of ER expression (mER), is very fast (Moriarty et al. 2006). Both the genomic rather than only the result of technical factors. Epigenetic and the non-genomic actions of estrogen are operative in regulation of ER expression was demonstrated in different benign and malignant thyroid cells (Manole et al. 2001). tumors including breast cancer (Hervouet et al. 2013). Alternatively, rapid signal transduction of estrogen may Moreover, both isoforms, ERa and ERb, were detected be mediated by a novel G protein-coupled receptor, in goiter tissues, thyroid carcinomas, and different thyroid designated GPR30 (Revankar et al.2005). This receptor has carcinoma cells (Manole et al. 2001, Santin & Furlanetto been detected in some thyroid carcinoma cell lines that lack 2011). Most of the thyroid cancer cell lines that are widely classical ERs and stimulate growth via GPR30 but not in used in thyroid research express both ER isoforms (Manole benign and malignant thyroid tissues (Vivacqua et al.2006). et al. 2001, Santin & Furlanetto 2011). However, similarly, http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-14-0053 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 05:56:17AM via free access Thematic Review M Derwahl and D Nicula Estrogen in thyroid cancer 21:5 T275 Table 1 Detection of estrogen receptors (ERs) a and b in benign and malignant thyroid tissues (ER-positive samples/total number of samples) Benign lesions Carcinoma Isoform Goiter Adenoma Papillary Follicular Anaplastic Methodology Molteni et al. (1981) ER 2/4 SDG Hampl et al. (1985) ER 0/5 RBA Haruta et al. (1990) ER 30/52 0/12 IHC Mizukami et al. (1991) ER 4/8 47/62 IHC Diaz et al. (1991) ER 20/30 23/30 11/20 IHC Hiasa et al.
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