Breast Cancer Abstracts 6

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Is iodine a gatekeeper of the integrity of the mammary gland
            (Aceves et al., 2005) Download
This paper reviews evidence showing iodine as an antioxidant and antiproliferative agent contributing to the integrity of normal mammary gland. Seaweed is an important dietary component in Asian communities and a rich source of iodine in several chemical forms. The high consumption of this element (25 times more than in Occident) has been associated with the low incidence of benign and cancer breast disease in Japanese women. In animal and human studies, molecular iodine (I(2)) supplementation exerts a suppressive effect on the development and size of both benign and cancer neoplasias. This effect is accompanied by a significant reduction in cellular lipoperoxidation. Iodine, in addition to its incorporation into thyroid hormones, is bound into antiproliferative iodolipids in the thyroid called iodolactones, which may also play a role in the proliferative control of mammary gland. We propose that an I(2) supplement should be considered as an adjuvant in breast cancer therapy.

Antineoplastic effect of iodine in mammary cancer: participation of 6-iodolactone (6-IL) and peroxisome proliferator-activated receptors (PPAR).
            (Aceves et al., 2009) Download
INTRODUCTION:  Studies in mammary cancer demonstrated that moderately high concentrations of molecular iodine (I2) have a antiproliferative and apoptotic effect either in vivo as in vitro, however the cellular intermediated involved in these effects has not been elucidated. METHODS:  Virgin Sprague-Dawley rats were treated with methyl-nitrosourea (MNU: single dose ip, 50 mg/Kg bw) and the participation of arachidonic acid (AA) and PPAR receptors in the antineoplasic effect of I2 where analyzed. RESULTS:  I2-treated rats for four weeks exhibited a significant reduction in the incidence (62.5 vs. 100%) and size (0.87 +/- 0.98 vs 1.96 +/- 1.5 cm3) of mammary tumors. HPLC analysis showed that tumoral but not normal mammary tissue contained an elevated basal concentration of AA and significantly more AA-iodinated called 6-iodolactone (6-IL) after chronic I2 treatment. Tumors from I2-treated rats showed fewer cells positive to proliferating cell nuclear antigen, lower blood vessel density, as well as decreases in vascular endothelial growth factor, urokinase-type plasminogen activator, and PPAR type alpha (PPARalpha). These same tumors showed increases in the cell death markers, TUNEL-positive cells (p < 0.05) and the enzyme caspase-3 (trend), as well as significant induction of PPAR type gamma (PPARgamma). CONCLUSION:  Together, these data demonstrate that the antineoplasic effect of iodine involves 6-IL formation and PPARgamma induction.

The extrathyronine actions of iodine as antioxidant, apoptotic, and differentiation factor in various tissues.
            (Aceves et al., 2013) Download
BACKGROUND:  Seaweed is an important dietary component and a rich source of iodine in several chemical forms in Asian communities. Their high consumption of this element (25 times higher than in Western countries) has been associated with the low incidence of benign and cancerous breast and prostate disease in Japanese people. SUMMARY:  We review evidence showing that, in addition to being a component of the thyroid hormone, iodine can be an antioxidant as well as an antiproliferative and differentiation agent that helps to maintain the integrity of several organs with the ability to take up iodine. In animal and human studies, molecular iodine (I2) supplementation exerts a suppressive effect on the development and size of both benign and cancerous neoplasias. Investigations by several groups have demonstrated that these effects can be mediated by a variety of mechanisms and pathways, including direct actions, in which the oxidized iodine dissipates the mitochondrial membrane potential, thereby triggering mitochondrion-mediated apoptosis, and indirect effects through iodolipid formation and the activation of peroxisome proliferator-activated receptors type gamma, which, in turn, trigger apoptotic or differentiation pathways. CONCLUSIONS:  We propose that the International Council for the Control of Iodine Deficient Disorders recommend that iodine intake be increased to at least 3 mg/day of I2 in specific pathologies to obtain the potential extrathyroidal benefits described in the present review.

Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection.
            (Alfaro et al., 2013) Download
BACKGROUND:  Although mammary cancer (MC) is the most common malignant neoplasia in women, the mortality for this cancer has decreased principally because of early detection and the use of neoadjuvant chemotherapy. Of several preparations that cause MC regression, doxorubicin (DOX) is the most active, first-line monotherapeutic. Nevertheless, its use is limited due to the rapid development of chemoresistance and to the cardiotoxicity caused by free radicals. In previous studies we have shown that supplementation with molecular iodine (I2) has a powerful antineoplastic effect in methylnitrosourea (MNU)-induced experimental models of MC. These studies also showed a consistent antioxidant effect of I2 in normal and tumoral tissues. METHODS:  Here, we analyzed the effect of I2 in combination with DOX treatment in female Sprague Dawley rats with MNU-induced MC. In the first experiment (short) animals were treated with the therapeutic DOX dose (16 mg/kg) or with lower doses (8 and 4 mg/Kg), in each case with and without 0.05% I2 in drinking water. Iodine treatment began on day 0, a single dose of DOX was injected (ip) on day 2, and the analysis was carried out on day 7. In the second experiment (long) animals with and without iodine supplement were treated with one or two injections of 4 mg/kg DOX (on days 0 and 14) and were analyzed on day 56. RESULTS:  At all DOX doses, the short I2 treatment induced adjuvant antineoplastic effects (decreased tumor size and proliferating cell nuclear antigen level) with significant protection against body weight loss and cardiotoxicity (creatine kinase MB, cardiac lipoperoxidation, and heart damage). With long-term I2, mammary tumor tissue became more sensitive to DOX, since a single injection of the lowest dose of DOX (4 mg/Kg) was enough to stop tumor progression and a second DOX4 injection on day 14 caused a significant and rapid decrease in tumor size, decreased the expression of chemoresistance markers (Bcl2 and survivin), and increased the expression of the apoptotic protein Bax and peroxisome proliferator-activated receptor type gamma. CONCLUSIONS:  The DOX-I2 combination exerts antineoplastic, chemosensitivity, and cardioprotective effects and could be a promising strategy against breast cancer progression.

The potential of iodine for improving breast cancer diagnosis and treatment.
            (Altman et al., 2013) Download
Early detection through modalities such as mammography remains pivotal in the fight against breast cancer. The detectability of breast cancer through mammography is rooted in the differential X-ray attenuation properties of cancerous and normal breast tissue. An unexplored component of the X-ray contrast between fibrous breast tissue and similarly composed tumor tissue is the presence of naturally localized iodine in the cancer but not healthy breast tissue. It is hypothesized that differing amounts of iodine are present in tumor versus normal breast tissue that leads to more easily detectable cancer due to an increased Z value of the tumor tissue relative to the healthy tissue, which results in enhanced differences in X-ray attenuation properties between the two tissues and thus greater radiographic contrast. The hypothesis is supported by experimental observations explaining how iodine could localize in the tumor tissue but not surrounding healthy tissue. Breast cancer cells express the sodium-iodide symporter (NIS), an ion pump which sequesters iodine in tumor cells. Healthy non-lactating breast tissue, in contrast, does not express NIS. Further evidence for the differential expression of NIS resulting in X-ray contrast enhancement in breast cancer is the established correlation between expression of insulin growth factor (IGF) and enhanced X-ray contrast, and the evidence that IGF is a promoter for NIS. Ultimately, if the expression of iodine can be shown to be a component of radiographic contrast between healthy and tumor breast tissue, this could be used to drive the development of new technology and techniques for use in the detection and treatment of breast cancer. The proof of this hypothesis could thus have a substantial impact in the fight against breast cancer.


Molecular pathways involved in pregnancy-induced prevention against breast cancer.
            (Barton et al., 2014) Download
Pregnancy produces a protective effect against breast cancer in women who had their first full term pregnancy (FTP) in their middle twenties. The later in life the first delivery occurs, the higher the risk of breast cancer development. Also, transiently during the postpartum period, the risk of developing breast cancer increases. This transient increased risk is taken over by a long-lasting protective period. The genomic profile of parous women has shown pregnancy induces a long-lasting "genomic signature" that explains the preventive effect on breast cancer. This signature reveals that chromatin remodeling is the driver of the differentiation process conferred by FTP. The chromatin remodeling process may be the ultimate step mediating the protection of the breast against developing breast cancer in post-menopausal years.

Activation of peroxisome proliferator-activated receptor gamma is crucial for antitumoral effects of 6-iodolactone.
            (Nava-Villalba et al., 2015) Download
BACKGROUND:  Molecular iodine (I2) exhibits antiproliferative and apoptotic effects on in vivo and in vitro cancer models. These effects are thought to be mediated by an iodinated arachidonic acid derivative, 6-iodolactone (6IL), and one of the proposed mechanisms is that 6IL activates Peroxisome Proliferator-Activated Receptors type gamma (PPARG). These receptors have been implicated in the inhibition of carcinogenic processes, in addition to their classical role in maintaining lipid and glucose homeostasis. The aim of this study was to determine whether PPARG participates in the 6IL antiproliferative and apoptotic effects on the mammary cancer cell line MCF-7. METHODS:  The 6IL/PPARG complex was inhibited by the PPARG antagonist GW9662, in both an endogenous and overexpressed (adenoviral vector infection) context, and stable PPARG-knockdown MCF-7 cells (RNA interference, confirmed with hydrolysis probes and Western blot), were used to corroborate the PPARG participation. 6IL effects on proliferation (measured by Trypan Blue exclusion) and apoptosis (phosphatidylserine identification by flow cytometer) were evaluated in conditions of chemical inhibition (GW9662) and silencing (RNA interference). A wound-healing assay was conducted on wild-type and stable PPARG-knockdown MCF-7 cells to evaluate the antimigrational effect of 6IL. Caspase-8 activity was evaluated to determine if the extrinsic pathway is involved in the effects of 6IL and I2 treatment. RESULTS:  Antiproliferative and pro-apoptotic 6IL effects require the activation of PPARG. In addition, wound-healing assays show that 6IL is able to inhibit MCF-7 cell migration and that PPARG plays a role in this phenomenon. Finally, the data exclude the participation of the extrinsic apoptotic pathway in 6IL- and I2-induced apoptosis. CONCLUSIONS:  These results support the previously proposed mechanism, in which the I2 effects are mediated by 6IL, and they provide further support for the use of I2 as coadjuvant in breast cancer treatment.

Changes in Dietary Iodine Explains Increasing Incidence of Breast Cancer with Distant Involvement in Young Women.
            (Rappaport, 2017) Download
The incidence of breast cancer with distant involvement at diagnosis is increasing in young women. The hypothesis that iodine deficiency in the United States, plays a role in the increased incidence of breast cancer with distant involvement, is discussed. Increased iodine demand in women is likely due to the increased uptake of iodine in breast tissue, in addition to the thyroid gland, where iodine plays a role in the development and maintenance of healthy breast tissue (expanding after puberty) and in breast remodeling during lactation, and pregnancy. According to the CDC’s 2012 Second National Report of Biochemical Indicators of Diet and Nutrition in the U.S. Population, women of childbearing age exhibited the lowest urinary iodine levels of any age group.

Antiproliferative/cytotoxic effects of molecular iodine, povidone-iodine and Lugol's solution in different human carcinoma cell lines.
            (Rösner et al., 2016) Download
Clinical trials have revealed that molecular iodine (I2) has beneficial effects in fibrocystic breast disease and in cyclic mastalgia. Likewise, povidone-iodine (PVP-I), which is widely used in clinical practice as an antiseptic agent following tumour surgery, has been demonstrated to have cytotoxic effects on colon cancer and ascites tumour cells. Our previous study indicated that the growth of breast cancer and seven other human malignant cell lines was variably diminished by I2 and iodolactones. With the intention of developing an iodine-based anticancer therapy, the present investigations extended these studies by comparing the cytotoxic capacities of I2, potassium iodide (KJ), PVP-I and Lugol's solution on various human carcinoma cell lines. Upon staining the cell nuclei with Hoechst 33342, the cell densities were determined microscopically. While KJ alone did not affect cell proliferation, it enhanced the antiproliferative activity of I2. In addition, PVP-I significantly inhibited the proliferation of human MCF-7 breast carcinoma, IPC melanoma, and A549 and H1299 lung carcinoma cells in a concentration corresponding to 20 µM I2. Likewise, Lugol's solution in concentrations corresponding to 20-80 µM I2 were observed to reduce the growth of MCF-7 cells. Experiments with fresh human blood samples revealed that the antiproliferative activity of PVP-I and I2 is preserved in blood plasma to a high degree. These findings suggest that PVP-I, Lugol's solution, and a combination of iodide and I2 may be potent agents for use in the development of antitumour strategies.


 

Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer.
            (Toniolo et al., 2010) Download
Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy.

 


References

Aceves, C, B Anguiano, and G Delgado (2005), ‘Is iodine a gatekeeper of the integrity of the mammary gland’, J Mammary Gland Biol Neoplasia, 10 (2), 189-96. PubMed: 16025225
Aceves, C, et al. (2009), ‘Antineoplastic effect of iodine in mammary cancer: participation of 6-iodolactone (6-IL) and peroxisome proliferator-activated receptors (PPAR).’, Mol Cancer, 8 33. PubMed: 19500378
Aceves, C, B Anguiano, and G Delgado (2013), ‘The extrathyronine actions of iodine as antioxidant, apoptotic, and differentiation factor in various tissues.’, Thyroid, 23 (8), 938-46. PubMed: 23607319
Alfaro, Y, et al. (2013), ‘Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection.’, Mol Cancer, 12 45. PubMed: 23705792
Altman, MB, et al. (2013), ‘The potential of iodine for improving breast cancer diagnosis and treatment.’, Med Hypotheses, 80 (1), 94-98. PubMed: 23171625
Barton, M, J Santucci-Pereira, and J Russo (2014), ‘Molecular pathways involved in pregnancy-induced prevention against breast cancer.’, Front Endocrinol (Lausanne), 5 213. PubMed: 25540638
Nava-Villalba, M, et al. (2015), ‘Activation of peroxisome proliferator-activated receptor gamma is crucial for antitumoral effects of 6-iodolactone.’, Mol Cancer, 14 168. PubMed: 26376791
Rappaport, J (2017), ‘Changes in Dietary Iodine Explains Increasing Incidence of Breast Cancer with Distant Involvement in Young Women.’, J Cancer, 8 (2), 174-77. PubMed: 28243321
Rösner, H, et al. (2016), ‘Antiproliferative/cytotoxic effects of molecular iodine, povidone-iodine and Lugol’s solution in different human carcinoma cell lines.’, Oncol Lett, 12 (3), 2159-62. PubMed: 27602156
Toniolo, P, et al. (2010), ‘Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer.’, Cancer Res, 70 (17), 6779-86. PubMed: 20713523