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SMYTH
Role of iodine in antioxidant defense in thyroid and breast disease.Smyth PP.
The role played in thyroid hormonogenesis by iodide oxidation to iodine (organification) is well established. Iodine deficiency may produce conditions of oxidative stress with high TSH producing a level of H2O2, which because of lack of iodide is not being used to form thyroid hormones. The cytotoxic actions of excess iodide in thyroid cells may depend on the formation of free radicals and can be attributed to both necrotic and apoptotic mechanisms with necrosis predominating in goiter development and apoptosis during iodide induced involution. These cytotoxic effects appear to depend on the status of antioxidative enzymes and may only be evident in conditions of selenium deficiency where the activity of selenium containing antioxidative enzymes is impaired. Less compelling evidence exists of a role for iodide as an antioxidant in the breast. However the Japanese experience may indicate a protective effect against breast cancer for an iodine rich seaweed containing diet. Similarly thyroid autoimmunity may also be associated with improved prognosis. Whether this phenomenon is breast specific and its possible relationship to iodine or selenium status awaits resolution.
"Iodine can react with double bonds on lipids such as polyunsaturated fatty acids rendering them less reactive to ROS. Polyunsaturated fatty acids such as arachidonic acid which is known to play a role in intracellular signalling in the thyroid contains four double bonds and can be easily oxidised and thus contribute to increased lipid peroxidation [32]. It has been postulated that formation of iodolipids such as iodolactones or iodoaldehydes represents a form of thyroidal autoregulation [33] which may be the mode of action of iodide inhibition of thyroidal function in the Wolff-Chaikoff effect [6,34,35]. While lower doses of iodide are necessary substrates for TPO mediated conversion into I2, iodinated compounds (so called XI) at high doses may exert inhibitory effects on adenylate-cyclase, NADPH-oxidase and TPO activities [6,35]. This effect seems to require oxidation of I− to I2 as inhibitors of TPO or I− trapping can reverse the inhibitory effect [35]."
"A role for iodide as an antioxidant possibly through a protective action of iodolipids as described for the thyroid has been suggested [6466]. This is on the basis of a shared iodide concentrating mechanism in both thyroid and breast as well as a requirement for an iodide oxidation system to provide for the formation of iodoamino acids leading to thyroid hormone formation in the thyroid and to iodinated milk proteins by the breast necessary for neonatal nutrition [5052]. Figure 3 shows in cartoon form the uptake of I− by the breast and its incorporation into iodoproteins. When taken into the breast I− is incorporated into lactoproteins presumably as a result of organification into I2 by lactoperoxidases [57,66]. These iodoproteins together with free I− are secreted in breast milk. As mentioned elsewhere in this communication, I− may also be incorporated into iodolipids such as iodolactones or iodoaldehydes which in the thyroid have been shown to possess antiproliferative properties. To date there is no evidence that a similar effect is produced in the breast."
The thyroid, iodine and breast cancer.Smyth PP. Breast Cancer Res. 2003;5(5):235-8. Epub 2003 Jul 29.
"A renewal of the search for a link between breast cancer and thyroid disease has once again demonstrated an increased prevalence of autoimmune thyroid disease in patients with breast cancer. This is the most recent of many studies showing an association between a variety of thyroid disorders and breast cancer. Such an association is not surprising as both diseases are female predominant with a similar postmenopausal peak incidence. The significance of the presence of thyroid autoantibodies, particularly thyroid peroxidase antibodies, in serum from patients with breast cancer is unknown, but it has been suggested that antibody positivity is associated with better prognosis. One area in which thyroid and breast functions overlap is in the uptake and utilization of dietary iodide. Experimental findings showing the ability of iodine or iodine-rich seaweed to inhibit breast tumour development is supported by the relatively low rate of breast cancer in Japanese women who consume a diet containing iodine-rich seaweed. However, there is as yet no direct evidence that iodine, iodinated compounds, or a combination of iodine and selenium is the antimammary carcinogenic element in the Japanese diet. It remains to be resolved whether the perceived breast cancer-thyroid disease relationship is thyroid or iodine related or, in the case of thyroid autoantibodies, is the consequence of an immune response to the carcinoma. Is this response breast specific and does it relate to iodine status? These and many other questions await resolution before a definitive role in the natural history of breast carcinoma can be assigned to the thyroid."
Tissue iodine content and serum-mediated 125I uptake-blocking activity in breast cancer.Kilbane MT, Ajjan RA, Weetman AP, Dwyer R, McDermott EW, O'Higgins NJ, Smyth PP.J Clin Endocrinol Metab. 2000 Mar;85(3):1245-50.
"In the thyroid, active transport of iodide is under control of the TSH-dependent Na+/I- symporter (NIS), whereas in the breast such control is less well understood. In this study, NIS expression was demonstrated by RT-PCR in 2 of 2 fibroadenomata and 6 of 7 breast carcinoma messenger ribonucleic acid isolates. In addition, mean total tissue iodine levels of 80.9 +/- 9.5 ng I/mg protein in 23 benign tumors (fibroadenomata) were significantly higher than those in 19 breast cancers taken from either the tumor (18.2 +/- 4.6 ng I/mg) or morphologically normal tissue taken from within the tumor-bearing breast (31.8 +/- 4.9 ng I/mg; P < 0.05 in each case). Inhibition of 125I uptake into NIS-transfected CHO cells was observed in serum from 20 of 105 (19.0%) breast carcinoma, 8 of 49 (16.3%) benign breast disease, and 27 of 86 (31.4%) Graves' patients, but in only 1 of 33 (3.0%) age-matched female controls. IgG purified from serum of patients showing positive 125I uptake inhibition also inhibited iodide uptake, suggesting that such inhibition was antibody mediated. 125I uptake inhibition was significantly associated with thyroid peroxidase antibody positivity (P < 0.05) in sera from breast cancer patients, but not in those with benign breast disease, once again suggesting an association between thyroid autoimmunity and breast carcinoma."
Autoimmune thyroid disease and breast cancer: a chance association?Smyth PP. J Endocrinol Invest. 2000 Jan;23(1):42-3. Review. [citation only]
Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma.Smyth PP, Shering SG, Kilbane MT, Murray MJ, McDermott EW, Smith DF, O'Higgins NJ. J Clin Endocrinol Metab. 1998 Aug;83(8):2711-6.
"The prevalence of thyroid peroxidase autoantibodies (TPO.Ab) was assessed in patients with either breast carcinoma or benign breast disease, and its association with disease outcome in breast carcinoma was studied. TPO.Ab were detected by direct RIA in serum from 121/356 (34.0%) of patients with breast carcinoma, compared with 36/194 (18.5%) of controls (P < 0.001); and in 31/108 (28.7%) with benign breast disease, compared with 12/88 (13.6%) of controls (P < 0.05). Survival analysis in a group of 142 women with breast carcinoma demonstrated that TPO.Ab titres > or = 0.3 U/mL were associated with a significantly better disease-free [relative risk (RR) = 1.84, P < 0.05] and overall survival (RR = 3.46, P < 0.02), compared with those who were TPO.Ab-negative. Better outcome associated with higher TPO.Ab titres was confined to those who had thyroid volumes within the intermediate range (10.1-18.8 mL) and did not further enhance the good outcome recorded when volumes were < or = 10.0 mL or > 18.8 mL. Multivariate survival analysis showed that both TPO.Ab and thyroid volume were independently associated with prognosis in breast carcinoma and that RRs for disease-free survival were of a similar order of magnitude to well-established prognostic indices such as axillary nodal status or tumor size. These findings supply evidence that manifestations of thyroid autoimmunity are associated with a beneficial effect on disease outcome in breast carcinoma and provide the strongest evidence to date of a biological link between breast carcinoma and thyroid disease."
The thyroid and breast cancer: a significant association?Smyth PP. Ann Med. 1997 Jun;29(3):189-91. [abstract only]
"The coincidence of thyroid disorders and
breast cancer has long been a subject of debate. Associations with
hyperthyroidism, hypothyroidism, thyroiditis and nontoxic goitre have
been reported. Although no convincing evidence exists of a causal role
for overt thyroid disease in breast cancer, the preponderance of
published work favours an association with hypothyroidism.
Geographical variations in the incidence of breast cancer have been
attributed to differences in dietary iodine intake and an effect of
iodide on the breast has been postulated. Recent reports have shown a
direct association between thyroid enlargement, as assessed by
ultrasound, and breast cancer. Although the exact mechanism for the
demonstrated association between diseases of the thyroid and breast
cancer remains to be elucidated, there is at least the possibility
that the presence of thyroid abnormalities may influence breast cancer
progression and this alone should stimulate awareness into the
coincidence of the two disorders."
A direct relationship between thyroid enlargement and breast cancer.Smyth PP, Smith DF, McDermott EW, Murray MJ, Geraghty JG, O'Higgins NJ. J Clin Endocrinol Metab. 1996 Mar;81(3):937-41. [abstract only]
"Despite extensive study, evidence to support a direct relationship between diseases of the thyroid and breast has not been established. In this study thyroid volume was assessed by ultrasound in 200 patients with breast cancer and 354 with benign breast disease. Results were compared to appropriate female control groups. Both mean thyroid volume (21.1 +/- 1.4 mL) and the percentage of individual patients with enlarged (> 18.0 mL) thyroid glands (41.5%) were significantly greater in the breast cancer group than equivalent values (13.2 +/- 0.5 mL and 10.5%, respectively) in age-matched controls (P < 0.01 in both cases). The mean thyroid volume of 14.5 +/- 0.34 mL in patients with benign breast disease was also significantly greater than that of 12.5 +/- 0.38 mL in younger controls (P < 0.01). The results support a direct association between breast cancer and increased thyroid volume as mean thyroid volumes and the percentage of individual patients with enlarged thyroid glands were similar in those studied both before (20.8 +/- 1.3 mL and 43.0%) and after (21.4 +/- 1.6 mL and 40.0%) therapies for breast cancer. Although there is no evidence that thyroid enlargement represents a risk factor for breast cancer, the results emphasize the importance of raising the consciousness of the coincidence of both disorders."
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