Effect of Anti-Thyroperoxidase on Thyroid Gland and Breast Tissue: A Comprehensive Review

Sabitha Kandi, Venkata Bharatkumar Pinnelli, Pragna Rao, K V Ramana

  Open Access OPEN ACCESS  Peer Reviewed PEER-REVIEWED

Effect of Anti-Thyroperoxidase on Thyroid Gland and Breast Tissue: A Comprehensive Review

Sabitha Kandi1,, Venkata Bharatkumar Pinnelli2, Pragna Rao3, K V Ramana4

1Department of Bio-chemistry, Chalmeda Anandarao Institute of Medical Sciences, Karimnagar, India

2Department of Bio-chemistry, Vaidehi Institute of Medical Sciences, and Research Centre, Bangalore, India

3Department of Bio-chemistry, Kasturba Medical College, Manipal Universiy, Manipal, India

4Department of Microbiology, Prathima Institute of Medical Sciences, Karimnagar, India

Abstract

Relationship between thyroid disease and breast tissue has long been debated as both the tissues have same embryological origin. Recent studies have implicated the possible role of thyroid dysfunction in the development and progression of breast related disorders. In view of increased prevalence of hypo and hyper thyroidism globally, there is a possibility of hormonal imbalance which may contribute to the initiation of tumor growth. Current literature has confirmed the role of sodium-iodide symporter (NIS) gene expression in breast cancers. Elevated anti-thyroperoxidase enzyme has been associated with increased risk of breast cancer. Activity of thyroid gland in post menopausal women, role of iodide levels and its relation to breast tissue and development of breast cancer needs extensive evaluation. In this comprehensive review we describe the role of NIS in thyroid gland functioning, thyroid hormone signaling mechanism.

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Cite this article:

  • Kandi, Sabitha, et al. "Effect of Anti-Thyroperoxidase on Thyroid Gland and Breast Tissue: A Comprehensive Review." American Journal of Medicine Studies 2.2 (2014): 34-37.
  • Kandi, S. , Pinnelli, V. B. , Rao, P. , & Ramana, K. V. (2014). Effect of Anti-Thyroperoxidase on Thyroid Gland and Breast Tissue: A Comprehensive Review. American Journal of Medicine Studies, 2(2), 34-37.
  • Kandi, Sabitha, Venkata Bharatkumar Pinnelli, Pragna Rao, and K V Ramana. "Effect of Anti-Thyroperoxidase on Thyroid Gland and Breast Tissue: A Comprehensive Review." American Journal of Medicine Studies 2, no. 2 (2014): 34-37.

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1. Introduction

Thyroid peroxidase (TPO) is a key enzyme in the synthesis of thyroid hormone. TPO is involved in the thyroid hormone synthesis (Organification and Coupling reactions). Iodide uptake is the critical step in thyroid hormone synthesis. Ingested iodine is bound to serum albumin and unbound iodine is excreted in urine. Iodide uptake is mediated by sodium iodide symporter(NIS), which is expressed at the basolateral region of thyroid follicular cells. NIS is expressed mostly in thyroid gland and leastly in salivary glands, lactating breast and placenta.

After iodide enters the thyroid, it is trapped and transported to the apical region of thyroid follicular cells. The oxidation of iodide to iodine is catalysed by the enzyme thyroid Peroxidase(TPO). This reaction requires H2O2 and NADPH, NADPH is from hexose mono phosphate(HMP) shunt pathway.

The reactive or active iodine atoms are added selectively to tyrosyl residues within thyroglobulin. The iodotyrosine residues of thyroglobulin are coupled via ether linkage catalysed by TPO. Further it leads to formation of T3 andT4, the thyroglobulin molecules are taken back into thyroid cell. The release of T3, T4 are by the action of lysosomal enzymes. Uncoupled Monoiodotyrosine (MIT) Diiodotyrosine(DIT) are deiodinated by dehalogenase or deiodinase, the iodine liberated is recycled for thyroid hormone synthesis (Figure 1).

Figure 1. Diagramatic sketch of NIS and thyroid hormone synthesis

Thyroid hormone acts by binding to thyroid hormone receptors(TR) α andβ. The α andβ subunits of these receptors are expressed in most tissues. TR is coupled to α subunit of G protein activates adenylate cylase, Increases the production of cyclic AMP. The receptor contain a central DNA binding domain, they bind to specific DNA sequences termed as thyroid response elements(TRE) in the promoter region of target genes. The receptors mostly bind as homodimers stimulate gene transcription or inhibition [1] (Figure 2).

Figure 2. Mechanism of Thyroid hormone signaling pathway and Receptor action

A rise of 26% in breast cancer i.e., about 1.7 million women will be affected by breast cabncer in 2020, mostly in developing countries [2, 3]. The progression of many human cancers including breast are known to be influenced by steroid hormones [4, 5]. The oestrogen hormone levels play an important role in growth and development of breast cancer [6, 7].

The complex interaction between genetic and environmental factors may lead to autoimmune thyroid diseases. The genes identified are HLA – DR gene locus, non – MHC genes such as CTLA – 4, CD40, PTPN22, Thyroglobulin and TSH receptor gene. The environmental factors includes low iodine content, infections, smoking, various medications and also due to stress [8]. It is reported by several authors that stress influences immune system and thus there is a relation between stress and worsening of autoimmune thyroid disorders [9]. The environmental factors, pathological conditions and physiological agents and hormone levels of thyroid gland influence the development of breast cancer [10]. Martinez et.al., reported that addition of thyroid hormones at physiological concentrations effects the proliferation of epithelial cells of breast tissue [11].

Thyroid hormone and oestrogen share similar pathways in regulating growth and proliferation of the cells in the target tissues, including cancer cells. The evaluation of presence of the receptors of these hormones is important in understanding the progression of the cancer [12, 13]. One of the recent study states that a change in the expression of the thyroid hormone receptors in breast cancer tissues, which says that these receptors are deregulated which in turn increases the risk for development of breast cancer [14, 15, 16].

A raise in serum anti –TPO levels is seen not only in breast cancer but also in goiter cases (8% diffuse 50% nodular). This findings show both increased goiter rates and increased thyroid enlargement by ultrasound in breast cancer patients [17, 18, 19]. Breast cancer and thyroid diseases predominantly affect females and that to post menopausal women which show an association between these two diseases [20, 21]. The presence of circulating TPO antibodies shows an increased risk for future hypothyroidism [22].

2. Relation between Functioning of Thyroid and Breast Tissues

The uptake and utilization of iodide by thyroid and breast tissue is similar. In the thyroid Iodide is required for the formation of T3 and T4. Iodide of breast helps in neonatal nutrition. There is no other role of iodide in breast tissue except acting as a nutrient in breast milk. In these orgens, iodine undergoes Organification (oxidize Iodide to iodine) to foirm iodoprotiens [23, 24]. This step requires the presence of H2O2 as an oxidizing agent catalyzed by TPO in the thyroid and by lactoperoxidases in the breast tissue. These iodoproteins / iodinated compounds inhibit the functions of thyroid gland by inhibiting the actions of adenylate cyclase, NADPH oxidase and TPO activities [25]. Thus, the inhibitory actions of these iodinated compounds play an important role in development of breast cancer [26, 27]. The tissue iodine levels are low in breast cancer than in normal/benign breast tumors [28].

In a survey conducted, it is found that breast cancer proceed to thyroid tumor. The survey concludes that breast and thyroid cancer occur at almost sametime, but the growth of breast cancer might be faster than that of thyroid tumors [29].

3. Discussion

Acetylation / deacetylatio0n and other modifications of histones lead to genetic alterations to the genome which proved to have a role in breast carcinogenesis [30]. Epigenetic alterations to the genome occur when there is deregulation of hormone signaling [31]. Several research findings reveal the proapototic potential of the thyroid hormone [32, 33, 34].

T3 levels in post menopausal women are positively associated with the risk of breast cancer. T3 in the circulation binds to thyroxin binding globulin (TBG), transthyretin and albumin. Increase in TBG leads to raised T3 levels. Increased TBG levels are seen in breast cancer, Hormone Replacement Therapy (HRT) and use of Oral Contraceptives (OC). Excluding HRT &OC also similar risk i.e., increase TBG levels are seen in breast cancer patients [35].

T3 binds and stimulates the estrogen receptor, acts in association with estrogen on breast cancer cell lines, potentiates estrogenic effect and enhances cell proliferation [36]. The role of estrogen in breast carcinogenesis is known and this high T3 levels would enhances the carcinogenic effect to breast tissue.

A study conducted by Cristofanilli et.al., reports that women with previous hypothyroid conditions are at increased risk for breast cancer.

Thyroid diseases such as Carcinoma, adenoma and adenomatous goitre have an influence on the carcinogenesis of breast [29]. The incidence of non – toxic goitre and thyroid swelling are high in breast cancer patients which supports the above said influence on breast tissue [37].

The raised anti TPO levels in autoimmune thyroid diseases are positively correlated with an increased risk for breast cancer. So, it is not clear whether the raised anti TPO antibodies is related to breast cancer or general autoimmune response of the body to malignancy [38].

The sodium / Iodide symporter (NIS) gene is expressed approximately 1/3rd of human breast cancer tissue. Its expression is independent of the hormonal receptor status of the patient (TSH-R gene, ER / PR) [39]. The studies on breast cancer patients indicates, an increased thyroid disorders in breast cancer patients, most commonly Hashimotos thyroiditis accounts to an increased thyroid disorders in these patients. This is independent of hormonal receptor status of the patient. These findings suggest the usefulness of screening for thyroid disease in any patient with breast cancer [40]. Alterations to expression of thyroid hormone receptors are found in breast cancer by several studies [10]. It suggests a role of thyroid hormone receptor in the progression of breast cancer.

It was reported that most thyroid neoplastic and normal tissues were positive for mRNA of both P450 aromatase and estrogen receptor, shows that human thyroid gland has a role in both estrogen synthesis and intracrine / paracrine estrogen responsiveness [42]. This indicates a possible association between breast disease and thyroid cancers [43].

4. Conclusion

The raised serum anti TPO antibodies, increased goiter rates, increased thyroid enlargement in breast cancer patients shows an association between these two organs. The increased serum anti TPO levels whether it is due to autoimmune response of the body to malignancy still remains to be clarified.

References

[1]  Harry Jameson, Anthony P. Weetman chapter 320: ‘ DISORDERS OF THYROID GLAND’. Harrison’s principles of Internal medicine: 16th edition, Mc Greaw Hill medical publishing division, Newyork, vol. II: pg: 2104-2127.
In article      
 
[2]  The Lancet, “Breast cancer in developing countries”, The Lancet, 374997010; 1567-2131.
In article      
 
[3]  Tfayali A, Temroz S, Marod RA, Shamseddine A (2010) Breast cancer in low and middle income countries; an emerging and challenging epidemic. Journal of Oncology 2010: 1-5.
In article      CrossRef
 
[4]  Kim JJ, Champan – DavisE (2010) Role of Progesterone in endometrial cancer. Semin Rerod Med 28: 81-90.
In article      CrossRef
 
[5]  Lewis – Wambi JS, Jardon VC (2009) Estrogen region of apoptosis: how can one hormone stimulate and inhibit? Breast cancer Res 11: 2006.
In article      
 
[6]  Mazumdar A, Wang RA, mishra SK, Adam L, Bagheri – Yarmand R, et.al., (2001) Transcriptional repression of estrogen receptor by metasis associated protein I corepressor. Nat cell boil 3(1): 30-7.
In article      
 
[7]  Mishra SK, Yang Z, Manzumdar A, Talukder AH, Larose L, et.al., (2004) Metastatic tumor antigen I short form (MTAIs)associates with casein kinase I gamma 2, an estrogen responsive kinase. Oncogene 23(25): 4422-9.
In article      CrossRef
 
[8]  Tomer Y, Huber A: The etiology of autoimmune thyroid disease: a story of genes and environment: J Autoimmun, 2009, May – Jun; 32 (3-4): 231-9.
In article      CrossRef
 
[9]  Giustanni E, Pinchera A, Fierabracci P, Roncella M, Fustanio L, Marnmolic, et. al.,: Thyroid autoimmunity in patients with malignant and benign breast diseases before surgery: Nat Clin Pract Endocrinol Metab, 2006 Dec; 2(12): 660-1.
In article      
 
[10]  Silva JM, Dominguez G, Gonzalez – Sanccho JM,Gracia JM, Silva J, et.al., (2002) Expression of thyroid hormone receptor / erbA genes is altered in human breast cancer. Oncogene 21: 4307-4316.
In article      CrossRef
 
[11]  Martrinez MB, Ruan M, LA Fizpatrick LA (2000) Altered response to thyroid hormones by prostate and breast cancer cells. Cancer chemother pharmacol 2000:45; 93-102.
In article      CrossRef
 
[12]  Mangelsdrof D, Thummel C, Beato M, Herrlich P, Schutz G, et.al., (1995) The nuclear receptor super family: the second decade. Cell 83:835-839.
In article      CrossRef
 
[13]  Pranati sar, Rosalima Peter, Bandita Rath, Alok Das Mohapatra, Sandip K, Mishra (2011). 3,3’5’ triiodo thyronine induces apoptosis in human breast cancer MCF-7 cells, Repressing SMP30 expression through negative thyroid response elements plos one 6(6):e20861.
In article      
 
[14]  Conde I, Paniagua R,Zamora J, Blanquez MJ, Fraile B, et.al., (2006) Influence of thyroid hormone receptors on breast cancer cell proliferation. Annals of Oncology 17:60-64.
In article      CrossRef
 
[15]  Cestari SH, Figueiredo NB, Conde SJ, Clara S, Katayama MLH et.al.,(2009) Influence of estradiol and triiodothyronine on breast cancer celllines proliferation and expression of estrogen and thyroid hormone receptors. Arq Bras Endocrinol Metab 53(7): 859-64.
In article      CrossRef
 
[16]  Guigon CJ, Kim DW, Willingham MC, Cheng S-Y (2011) Mutation of the thyroid hormone receptor - β in mice predisposes to the development of mammary tumors. Oncogene 1-10.
In article      
 
[17]  Bogardus GM, Finley JW: Breast cancer and thyroid disease. Surgery 1961, 49; 461-468.
In article      
 
[18]  Adamopoulos DA, Vassilarus S, Kapolla N, Papadiamantis J, Georgiakodis F, Michalkis A: Thyroid disease in patients with benign and malignant mastopathy. Cancer 1986, 57: 125-128.
In article      CrossRef
 
[19]  Smyth PPA, Smith D, Mcdermott E, Murray M, Geraghty J, O’Higgins N: A direct relationship between thyroid enlargement and breast cancer. J Clin Endocrinol Metab 1996, 81: 937-941.
In article      
 
[20]  Goldman ME: Thyroid diseases and breast cancer. Epidemiol Rev 1990; 16-28.
In article      
 
[21]  Smyth PPa: The thyroid and breast cancer: a significant association? (Editorial). Ann Med 1997; 29: 189-191.
In article      CrossRef
 
[22]  Vanderpump Mp J, Tunbridge WMG: the epidemiology of autoimmune thyroid disease. In Contemporary Endocrinology Autoimmune Endocrinopathies. Edited by Volpe r. Totowa NJ; Humana Press; 1999: 141-162.
In article      
 
[23]  Taurog A: Hormone synthesis: thyroid iodine metabolism. In Werner and Ing ber’s the thyroid. Edited by Braverman L, Utiger RD. Philadelphia: Lippincott Co; 1996 47-81.
In article      
 
[24]  Shah NM, Eskin BA, Krouse TB, Sparks CE: Iodoprotein formation by rat mammary glands during pregnancy and early post partum period. Proc soc Exp Biol Med 1986, 181: 443-449.
In article      CrossRef
 
[25]  Denef JF, Many MC, Van den Hove MF: Iodine induced thyroid inhibition and cell necrosis: two consequences of the same free – radical mediated mechanis? Mol Cell Endocrinol 1996, 121: 101-103.
In article      CrossRef
 
[26]  Venturi S: Is there a role for iodine in breast diseases? The Breast 2001, 10: 379-382.
In article      CrossRef
 
[27]  Cann SA, Van Netten JP, Van Netten C: Hypothesis: Iodine, selenium and the development of breast cancer. Cancer causes control 2000, 11; 121-127.
In article      CrossRef
 
[28]  Kilbane MT, Ajjan RA, Weetman AP, Dwyer R, Mc Dermott EVM, O’Higgins NJ, Smyth PPA: Tissue iodine content and serum mediated I125 uptake blocking activity in breast cancer. J Clin Endocrinol Metab 2000, 85: 1245-1250.
In article      
 
[29]  Yoshinori Nio, Chikage iguchi, Masayuki itakura, Tomoko Toga, Koji Hasimoto et. al.,: High incidence of synchronous or metachronous breast cancer in patients with malignant and benign thyroid tumor or tumor – like disorders. Anticancer Research 2009, 29: 1607-1610.
In article      
 
[30]  Elsheikh SE, Green AR, Rakha EA, Powe DG, Ahmed RA et.al., (2009) Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 69(9): 3802-9.
In article      CrossRef
 
[31]  Diaz – Cruz ES, Furth PA (2010) Deregulated estrogen receptor α and p53 heterozygosity collaborate in the development of mammary hyperplasia: Cancer Res 62: 61-76.
In article      
 
[32]  Narayanan CH, Narayanan Y, Browne RC (1986) Development of the spinal tract of the trigeminal nerve and its relation to early foetal behavior in rats under normal and hypothyroid conditions. Exp Brain Res 62: 61-76.
In article      CrossRef
 
[33]  Mihara S, Suzuki N, Wakisaka S, Suzuki N, Wakisaka S, et.al., (1999) Effects of thyroid hormones on apoptotic cell death of human lymphocytes. J Clin Endocrinol Metab 84: 1378-1385.
In article      
 
[34]  Hara M, Suzuki S, Mori J, Yamashita K, Kumagai M et.al.,(2000). Thyroid hormone regulation of apoptosis induced by retinoic acid in promyeloleukemic HL – 60 cells studies with retinoic acid receptor specific and retinoid X – receptor specific ligands. Thyroid 10: 1023-1024.
In article      CrossRef
 
[35]  Utiger RD: Estrogen, thyroxine binding in serum and thyroxine therapy. N Eng J Med 2001, 344: 1784.
In article      CrossRef
 
[36]  Hall LC, Salazar Ep, Kane SR, Liu N: Effects of thyroid hormones on human breast cancer cell proliferation. J steroid Biochem Mol Biol 2008, 109: 57-66.
In article      CrossRef
 
[37]  Shering SG, Zbar AP, Moriarty M, Mc Dermott EW, O’Higgins NJ and smyth PP: Thyroid disorders and breast cancer. Eur J Cancer Prev 5: 504-506, 1996.
In article      
 
[38]  Smyth PP: the thyroid, iodine and breast cancer. Breast cancer Res 2003, 5: 235-238.
In article      CrossRef
 
[39]  Oh HJ, Chung JK, Kang JH, Kang WJ, Noh DY, Park IA, et. al.,: The relationship between expression of the sodium / iodide symporter gene and the status of hormonal receptors in human breast cancer tissue: Cancer Res Treat, 2005, Aug; 37(4); 247-50. Epub 2005 Aug 31.
In article      CrossRef
 
[40]  Giani C, Fierabracci P, Bonacci R, Gigliotti A, Campani D, De Negri F, et.al.,: Relationship between breast cancer and thyroid disease; relevance of autoimmune thyroid disorders in breast malignancy: J Clin Endocrinol Metab. 1996 Mar, 81(3): 990-4.
In article      
 
[41]  Dalla Valle L, Ramina A, Vianello S, Fassina A, Belverdere P and Colombo L: Potential for estrogen synthesis and action in human normal and neoplastic thyroid tissues. J Clin Endocrinol Metab 83: 3702-3709, 1998.
In article      
 
[42]  Sabitha, Suneetha, Shruthi Mohanty, Pragna Rao. Serum anti-TPO levels in benign and malignant breast tumors. Indian Journal of Clinical Biochemistry 2009 / 24 (3) 266-268.
In article      
 
[43]  Kandi S, Rao P. Anti-thyroid peroxidase antibodies: Its effect on thyroid gland and breast tissue. Ann Trop Med Public Health 2012; 5: 1-2.
In article      CrossRef
 
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