Venturi S. Servizio di Igiene, ASL n1, Regione Marche, Pennabilli (Pesaro), Italy. firstname.lastname@example.org
It is hypothesized that dietary iodine deficiency is associated with the development of mammary pathology and cancer. A review of the literature on this correlation and of the author's own work on the antioxidant function of iodide in iodide-concentrating extrathyroidal cells is reported. Mammary gland is embryogenetically derived from primitive iodide-concentrating ectoderm, and alveolar and ductular cells of the breast specialize in uptake and secretion of iodine in milk in order to supply offsprings with this important trace-element. Breast and thyroid share an important iodide-concentrating ability and an efficient peroxidase activity, which transfers electrons from iodide to the oxygen of hydrogen peroxide, forming iodoproteins and iodolipids, and so protects the cells from peroxidative damage. The mammary gland has only a temporary ability to concentrate iodides, almost exclusively during pregnancy and lactation, which are considered protective conditions against breast cancer.
IS THERE A ROLE FOR IODINE IN BREAST DISEASES?
Sebastiano Venturi, Servizio di Igiene, ASL n.1, Regione Marche; Pennabilli (Pesaro), Italy
Dr. Sebastiano Venturi via Tre Genghe n. 2 ; 47864 - Pennabilli (Italy) Tel: (+39) 0541 928205 . Fax: (+39) 0541 928112 .
It is hypothesized that dietary iodine deficiency is associated with the development of mammary pathology and cancer. A review of the literature on this correlation and of the author's own work on the antioxidant function of iodide in iodide-concentrating extrathyroidal cells is reported. Mammary gland embryogenetically derived from primitive iodide-concentrating ectoderma, and alveolar and ductular cells of the breast specialize in uptake and secretion of iodine in milk in order to supply offsprings with this important trace-element. Breast and thyroid share an important iodide-concentrating ability and an efficient peroxidase activity, which transfers electrons from iodides to the oxygen of hydrogen peroxide, forming iodoproteins and iodolipids, and so protects the cells from peroxidative damage. The mammary gland has only a temporary ability in concentrating iodides, almost exclusively during pregnancy and lactation, which are considered protective conditions against breast cancer.
Iodine is the richest in electrons of the required elements in the animal diet. In humans the total amount of iodine is about 30-50 mg and about 60%-80 % of total iodine is non-hormonal and it is concentrated in extrathyroidal tissues, where its biological role is still unknown. We have recently hypothesized that iodide might have an ancestral antioxidant function in all iodide-concentrating cells (1-5). In these cells iodide acts as an electron donor in the presence of H2O2 and peroxidase, and the remaining iodine atom readily iodinates tyrosine, histidine or certain specific lipids. In fact, iodine can add to double bonds of some polyunsaturated fatty acids of cellular membranes, making them less reactive to free oxygen radicals (6-7). Isolated cells of extrathyroidal tissues of mice could produce "in vitro" protein-bound mono-iodotyrosine, di-iodotyrosine and also other iodocompounds which seem to be iodolipids during chromatography (8). According to Cann et al. (9) iodolipids are present and active also in mammary cells.
IODINE AND BREAST ANATOMY AND PHYSIOLOGY
In the Mammal, iodide uptake has been demonstrated in various extrathyroidal tissues, including salivary gland, gastric mucosa, and the lactating mammary gland (10-11). Sodium iodide symporter (NIS) is the proteic transmembrane transporter of iodide. Cloning and molecular characterization of the human NIS have been recently performed. (12-13). The mammary gland has a high but temporary ability to concentrate iodides and to form iodocompounds (9,14) in alveolar and ductular cells by specific peroxidases (15), almost exclusively during pregnancy and lactation, which are considered protective conditions against breast cancer. In fact, during pregnancy and lactation, hormonal stimulation of the breast leads to glandular differentiation with dramatically enhanced iodine adsorption and organification (14). It is interesting to note that this iodine adsorption occurs in the same ductal epithelium (9, 16-17) where the majority of breast cancer arise. Lactoperoxidases, which are particularly active during pregnancy and lactation, organifies iodide in the breast. According to Eskin (18), iodine plays an important role in the maintenance of both normal thyroid and breast physiology. Recently, a second pathway for iodine organification has been described, which involves iodine incorporation into specific lipid molecules (polyunsaturated fatty acids). These iodolipids have been shown to be regulators of thyroid cells metabolism and proliferation. In particular 6-iodo-5-hydroxy-eicosatrienoic acid (delta-iodolactone) has been found to be a potent inhibitor of thyroid cells proliferation (19-21) and according to Cann et al. (9) these iodolipids may also play a role in anti-proliferative control of breast tissue. Tazebay et al. (22) reported that expression of NIS in normal mammary tissues is stimulated by oxytocin, which is released during lactation. In ovariectomized rats, a combination of estrogen, oxytocin and prolactin (PRL) led to maximal NIS expression in mammary cells. But what role does iodide play in mammary cells? We may chronologically differentiate (2, 4-5) on the basis of the phylogenesis and embryogenesis two possible mechanisms of action of iodine: 1) the first is more ancient acting directly on mammary cells which embryologically originate from iodide-concentrating ectoderma and epidermis, with iodide in mammary cells acting probably as antioxidant. 2) the second mechanism of action is more modern, wit iodine acting indirectly via thyroid hormones and their specific nuclear receptors. Hormonal imbalances can cause dysfunction of mammary glands. Rat mammary gland is able to take up (via NIS) and organically bind radioiodide. Iodination was not detected in mammary glands from non-pregnant rats. Protein-containing vacuoles in alveolar cells and casein-like proteins in milk are the major sites where iodination occurred within the gland. Milk proteins in the lumens of ductules adjacent to alveoli are also iodinated. Endogenous mammary peroxidases correlate with the ability to iodinate. In contrast, ducts, myoepithelial cells, fat cells, blood vessels and other histological components of the gland did not show iodinating capability (15).
IODINE AND BREAST PATHOLOGY
Eskin (16) reported that iodine is a prerequisite for the normal development of breast tissue in higher vertebrates. When lacking, the parenchyma in rodents and humans show atypia, dysplasia, and even neoplasia; in fact breast tissues are more susceptible to carcinogen action. In iodide- deficient rats Strum (17) also reported that atrophy, necrosis and also areas of dysplasia and atypia take place in the mammary gland, which becomes highly sensitive to stimulation by oestradiol. In this way, oestradiol stimulates cell division and leads to the formation of alveoli with great quantities of lipid and protein droplets in large vacuoles which subsequently leads to the formation of cysts within the mammary gland. Eskin and coworkers (18, 23-26) reported a marked hyperplasia and papillomatosis of mammary ducts from rat given oestrogen in presence of disturbed thyroid-iodine metabolism and also a periductal fibrosis similar to that seen naturally in so-called fibrocystic disease of women. Dietary replacement therapy of iodine is able to improve these alterations in mammary tissue. Ghent et al. (27) reported that 70% of of women with fibrocystic breast disease orally treated with sodium iodide had clinical improvement in their breast disease. A decrease or loss of NIS expression may represent an early abnormality of thyroid (28) and breast (29) carcinogenesis rather than this occurring as a consequence of cancer progression. Statistical correlations between dietary iodine, thyroid diseases and breast cancer have been carried out by Ellerker (30), Stadel (31), Serra-Majem et al. (32), Smyth et al.(33) Giani et al.(34), Vassilopoulou- Sellin et al. (35) and Cann et al. (9). There is epidemiological evidence of the protective role against breast cancer of dietary fish (rich in iodine) (36-39) and n-3 polyunsaturated fatty acids, in which specific double bonds are protected by iodine from peroxidation. (6-7). Japanese women who have the highest iodine intake (4-10 mg /daily / per person) have the lowest rate of breast cancer mortality in the world. In fact populations of Japan frequently eat a notable quantity of marine algae (seaweed), which are very rich in iodine (40-41), whereas RDA (recommended dietary allowance) of iodine is 150-200 micrograms per day. Recently, many researchers studied NIS in mammary gland. Tazebay et al. (22) reported that mammary NIS may be an essential breast cancer marker and that radioiodide should be studied as having a possible role in the diagnosis and treatment of breast cancer. Kilbane et al. (42) demonstrated NIS expression in benign fibroadenomata and breast carcinoma, but total tissue iodine levels in benign tumours were significantly higher than those in breast cancers taken from either the tumor or morphologically normal tissue taken from within the tumour-bearing breast. Kogai et al. (43) reported that the NIS stimulates iodide uptake in normal lactating breast, but is not known to be active in nonlactating breast or breast cancer. Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in breast cancer cells. So, stimulation of radioiodide uptake after systemic retinoid treatment could be useful for diagnosis and treatment of some differentiated breast cancers. Rillema et al. (44) have shown that iodide accumulates in milk at higher concentration than in maternal plasma and that PRL enhances iodide accumulation in cultured mammary tissues, via stimulation of NIS. Cho et al. (45) suggested that iodine uptake and NIS expression in mammary gland are modulated by hormones involved in active lactation. NIS is clustered on the basolateral membrane of alveolar cells. The iodine uptake of lactating mammary gland is partially inhibited by treatment with a selective oxytocin antagonist or bromocriptine, an inhibitor of PRL release.
IODINE AND THYROID HORMONE IN THE THERAPY OF BREAST DISEASES
Beatson (46) reported adjuvant use of thyroid extract in some breast cancers in the "Lancet", as far back as 1896. Ghent et al. (26) reported that iodine treatment of women with benign breast disease caused a significant bilateral reduction in breast size, in addition to causing a remission of disease symptoms. Eskin and co-workers (47-48) showed a mammary tumor reduction in rats after iodine treatment. Some researchers found that the seaweed-supplemented diet (rich in iodine) is associated with an inhibition and delay in development of mammary cancer in rats (49-51). Funahashi et al. reported recently that both Japanese edible Wakame seaweed (52) and also a direct uptake of inorganic iodine (53) by tumor has experimentally a suppressive effect on DMBA-induced breast tumors growth in the rat. NIS expression is inversely related to undifferentiation, malignity and it is directly related to likelihoodof therapeutic effectiveness of radioiodine therapy. Recent studies reported that genetic characterisation and induction of the human NIS gene allows the development of novel gene therapy also for treatment of extrathyroidal and mammary malignancies (54). In fact, targeted expression of functional NIS in undifferentiated cancer cells would enable these cells to concentrate iodine and would therefore offer the possibility of radioiodine therapy (55-56). Boland et al. (57) propose to enlarge the therapeutic strategy to nonthyroid tumors by using an adenoviral vector to deliver the NIS gene into the tumor cells for a targeted radiotherapy.
In conclusion, the thyroid is not the only organ known to organify iodide and forming Iodocompounds. There is evidence for extrathyroidal iodide-concentrating organs, including the lactating breast and stomach. The knowledge of this iodinating ability and of the antioxidant and antitumour activity of iodide might be useful for helping to prevent breast cancer and also as a novel gene to allow radioiodine therapy to be given to patients with breast cancer (58). The extrathyroidal actions of iodide are an important new area for investigation.
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