Several groups, including ours, have reported that iodine exhibited antiproliferative and apoptotic effects in various cancer cells only if this element is supplemented as molecular iodine, or as iodide, to cells that are able to oxidize it with the enzyme thyroperoxidase. In this study, we analyzed the effect of various concentrations of iodine and/or iodide in the dimethylbenz[a]anthracene (DMBA) mammary cancer model in rats. The results show that 0.1% iodine or iodide increases the expression of peroxisome proliferator-activated receptor type γ (PPARγ), triggering caspase-mediated apoptosis pathways in damaged mammary tissue (DMBA-treated mammary gland) as well as in frank mammary tumors, but not in normal mammary gland. DMBA treatment induces the expression of lactoperoxidase, which participates in the antineoplastic effect of iodide and could be involved in the pro-neoplastic effect of estrogens, increasing the formation of DNA adducts. In conclusion, our results show that a supplement of 0.1% molecular iodine/potassium iodide (0.05/0.05%) exert antineoplastic effects, preventing estrogen-induced DNA adducts and inducing apoptosis through PPARγ/caspases in pre-cancer and cancerous cells. Since this iodine concentration does not modify the cytology (histology, apoptosis rate) or physiology (triiodothyronine and thyrotropin) of the thyroid gland, we propose that it be considered as an adjuvant treatment for premenopausal mammary cancer.
Ofelia Soriano, Guadalupe Delgado, Brenda Anguiano, Pavel Petrosyan, Edith D Molina-Servín, Maria E Gonsebatt, and Carmen Aceves
Shu Zhang, Ping Lei, Xinyi Liu, Xiangrong Li, Kelcey Walker, Leela Kotha, Craig Rowlands, and Stephen Safe
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the relatively non-toxic selective aryl hydrocarbon receptor (AhR) modulator 6-methyl-1,3,8-trichlorodibenzo-furan (MCDF) induced CYP1A1-dependent ethoxyresorufin O-deethylase activity and inhibited proliferation of seven estrogen receptor (ER) negative breast cancer cell lines. MCDF, TCDD and structurally related 2,3,7,8-tetrachlorodibenzofuran, 1,2,3,7,8-pentachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3′,4,4′,5-pentachlorobiphenyl induced CYP1A1 and inhibited proliferation of BT-474 and MDA-MB-468 cells. In BT474 and MDA-MB-468 cells transfected with a small inhibitory RNA for the AhR, the antiproliferative activity of the chlorinated aromatic compounds was reversed, whereas for MCDF, only partial reversal was observed, suggesting that this compound acts through both AhR-dependent and AhR-independent pathways in these two cell lines. MCDF also inhibited tumor growth in athymic nude mice in which MDA-MB-468 cells were injected directly into the mammary fat pad. These results suggest that the AhR is a potential drug target for treatment of ER-negative breast cancer.
T Suzuki, S Hayashi, Y Miki, Y Nakamura, T Moriya, A Sugawara, T Ishida, N Ohuchi, and H Sasano
It has been reported that agonists of peroxisome proliferator-activated receptor γ (PPARγ) inhibit proliferation of breast carcinoma cells, but the biological significance of PPARγ remains undetermined in human breast carcinomas. Therefore, we immunolocalized PPARγ in 238 human breast carcinoma tissues. PPARγ immunoreactivity was detected in 42% of carcinomas, and was significantly associated with the status of estrogen receptor (ER) α, ERβ, progesterone receptor, retinoic X receptors, p21 or p27, and negatively correlated with histological grade or cyclooxygenase-2 status. PPARγ immunoreactivity was significantly associated with an improved clinical outcome of breast carcinoma patients by univariate analysis, and multivariate analysis demonstrated that PPARγ immunoreactivity was an independent prognostic factor for overall survival in ERα-positive patients. We then examined possible mechanisms of modulation by PPARγ on estrogenic actions in MCF-7 breast carcinoma cells. A PPARγ activator, 15-deoxy-Δ12,14- prostaglandin J2 (15d-PGJ2), significantly inhibited estrogen-responsive element-dependent transactivation by estradiol in MCF-7 cells, which was blocked by addition of a PPARγ antagonist GW9662. Subsequent study, employing a custom-made microarray focused on estrogen-responsive genes, revealed that mRNA expression was significantly regulated by estradiol in 49 genes, but this significance vanished on addition of 15d-PGJ2 in 16 out of 49 (33%) genes. These findings were confirmed by real-time PCR in 11 genes. 15d-PGJ2 significantly inhibited estrogen-mediated proliferation of MCF-7 cells, and caused accumulation of p21 and p27 protein. These results suggest that PPARγ is mainly expressed in well-differentiated and ER-positive breast carcinomas, and modulates estrogenic actions.
Lei Quan, Chi-Chen Hong, Gary Zirpoli, Michelle R Roberts, Thaer Khoury, Lara E Sucheston-Campbell, Dana H Bovbjerg, Lina Jandorf, Karen Pawlish, Gregory Ciupak, Warren Davis, Elisa V Bandera, Christine B Ambrosone, and Song Yao
It has been observed previously that compared with women of European ancestry (EA), those of African ancestry (AA) are more likely to develop estrogen receptor (ER)-negative breast cancer, although the mechanisms have not been elucidated. We tested the associations between breast cancer risk and a targeted set of 20 genes known to be involved in estrogen synthesis, metabolism, and response and potential gene–environment interactions using data and samples from 1307 EA (658 cases) and 1365 AA (621 cases) participants from the Women’s Circle of Health Study (WCHS). Multivariable logistic regression found evidence of associations with single-nucleotide polymorphisms (SNPs) in the ESR1 gene in EA women (rs1801132, odds ratio (OR)=1.47, 95% CI=1.20–1.80, P=0.0002; rs2046210, OR=1.24, 95% CI=1.04–1.47, P=0.02; and rs3020314, OR=1.43, 95% CI=1.19–1.70, P=0.00009), but not in AA women. The only other gene associated with breast cancer risk was CYP1A2 in AA women (rs2470893, OR=1.42, 95% CI=1.00–2.02, P=0.05), but not in EA women. When stratified by ER status, ESR1 rs1801132, rs2046210, and rs3020314 showed stronger associations in ER-positive than in ER-negative breast cancer in only EA women. Associations with the ESR1 SNPs in EA women also appeared to be stronger with longer endogenous estrogen exposure or hormonal replacement therapy use. Our results indicate that there may be differential genetic influences on breast cancer risk in EA compared with AA women and that these differences may be modified by tumor subtype and estrogen exposures. Future studies with a larger sample size may determine the full contribution of estrogen-related genes to racial/ethnic differences in breast cancer.
Flavia Magri, Valentina Capelli, Mario Rotondi, Paola Leporati, Luigi La Manna, Rubina Ruggiero, Alberto Malovini, Riccardo Bellazzi, Laura Villani, and Luca Chiovato
Estrogen receptor (ER) and androgen receptor (AR) may be expressed in thyroid tumors, but their prognostic role is controversial. We investigated whether ER and AR expressions could confer a more aggressive phenotype to thyroid tumors. We enrolled 91 patients (13 males and 78 females, mean age 49.3±14.8 years) bearing small (T1 in the 2006 TNM system) differentiated thyroid cancers (DTC). Thirty-eight tumors were incidental histological findings. Using immunohistochemistry, we evaluated ERα, ERβ, and AR expressions in tumors and in its correspondent extra-tumor parenchyma. In tumors, 13 (16.7%) women and one (7.7%) man expressed ERα; 42 (53.8%) women and six (46%) men expressed ERβ; and 16 (20.5%) women and three (23.1%) men expressed AR. In normal thyroid parenchymas, ERβ was expressed in 52 (66.7%) women and nine (69.2%) men, ERα in three (3.8%) women, and AR in 13 (16.7%) women. Compared with normal thyroid parenchyma, tumors gained ERα and lost ERβ expressions. Incidental cancers were more commonly ERα(−) than ERα(+) (47.7 vs 14.3%, P=0.037). Postsurgical serum thyroglobulin was higher in ERα(+) tumors than in the ERα(−) tumors (P=0.04). ERβ(−) tumors showed vascular invasion more frequently than the ERβ(+) tumors (26.2 vs 4.1%, P=0.005). AR(+) tumors showed capsular invasion more frequently than the AR(−) tumors (77.8 vs 46.6%, P=0.014). In conclusion, ERα positivity, ERβ negativity, and AR expressions are associated with a more aggressive phenotype of small T1-DTC. ER and AR expressions may represent an additional criterion in deciding whether to perform radioiodine ablation in these tumors.
Cameron M Armstrong, Autumn R Billimek, Kimberly F Allred, Joseph M Sturino, Brad R Weeks, and Clinton D Allred
Postmenopausal women on estrogen replacement therapy (ERT) have a reduced risk of developing colon cancer compared with postmenopausal women not on ERT, suggesting a role for estradiol (E2) in protection against this disease. To determine whether E2 protects against inflammation-associated colon cancer when administered following the initiation of colonic DNA damage, in this study, we implanted E2-containing pellets into mice after co-treatment with azoxymethane and two rounds of dextran sulfate sodium (DSS). Wild-type (WT) E2-treated mice had reduced numbers and average area of adenocarcinomas compared with the control mice. These effects were lost in estrogen receptor-β (Er β (Esr2)) knockout mice. Surprisingly, apoptosis was reduced and cell proliferation was increased in sections from tumors of the WT E2 mice compared with the WT control mice. These findings are probably due, in part, to a reduction in ERβ expression in colonic epithelial cells as the cells progressed from a non-malignant to a cancerous state as enhanced apoptosis was observed in normal colonocytes expressing higher levels of ERβ. Furthermore, epithelial cells within the tumors had dramatically increased ERα mRNA and protein expression compared with the non-diseased mice. We conclude that while E2 treatment resulted in an overall suppression of colonic adenocarcinoma formation, reduced ERβ expression accompanied by enhanced ERα expression caused an altered colonocyte response to E2 treatment compared with the earlier stages of colon cancer development. These data are the first examples of decreased ERβ expression concurrent with increased ERα expression as a disease develops and highlight the importance of understanding the timing of E2 exposure with regard to the prevention of inflammation-associated colon cancer.
Ju-Yeon Moon, Man Ho Choi, and Jayoung Kim
Cholesterol and sex steroid hormones including androgens and estrogens play a critical role in the development and progression of urological diseases such as prostate cancer. This disease remains the most commonly diagnosed malignant tumor in men and is the leading cause of death from different cancers. Attempts to understand the role of cholesterol and steroid metabolism in urological diseases have been ongoing for many years, but despite this, our mechanistic and translational understanding remains elusive. In order to further evaluate the problem, we have taken an interest in metabolomics; a discipline dedicated to the systematic study of biologically active metabolites in cells, tissues, hair and biofluids. Recently, we provided evidence that a quantitative measurement of cholesterol and sex steroid metabolites can be successfully achieved using hair of human and mouse models. The overall goal of this short review article is to introduce current metabolomic technologies for the quantitative biomarker assay development and also to provide new insight into understanding the underlying mechanisms that trigger the pathological condition. Furthermore, this review will place a particular emphasis on how to prepare biospecimens (e.g., hair fiber), quantify molecular profiles and assess their clinical significance in various urological diseases.
E J S√°nchez-Barcel√≥, S Cos, R Fern√°ndez, and M D Mediavilla
Melatonin is an indolic hormone produced mainly by the pineal gland. The former hypothesis of its possible role in mammary cancer development was based on the evidence that melatonin down-regulates some of the pituitary and gonadal hormones that control mammary gland development and which are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, as a naturally occurring antiestrogen, thereby influencing their proliferative rate. The first reports revealed a low plasmatic melatonin concentration in women with estrogen receptor (ER)-positive breast tumors. However, later studies on the possible role of melatonin on human breast cancer have been scarce and mostly of an epidemiological type. These studies described a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impairment. Since light inhibits melatonin secretion, the relative increase in the melatonin circulating levels in women with a decreased light input could be interpreted as proof of the protective role of melatonin on mammary carcinogenesis. From in vivo studies on animal models of chemically induced mammary tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland or the administration of melatonin lengthens the latency and reduces the incidence and growth rate of mammary tumors, while pinealectomy usually has the opposite effects. Melatonin also reduces the incidence of spontaneous mammary tumors in different kinds of transgenic mice (c-neu and N-ras) and mice from strains with a high tumoral incidence. In vitro experiments, carried out with the ER-positive MCF-7 human breast cancer cells, demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol: (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastasic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness; this effect is mediated, at least in part, by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and beta(1)-integrin. The direct oncostatic effects of melatonin depends on its interaction with the tumor cell estrogen-responsive pathway. In this sense it has been demonstrated that melatonin down-regulates the expression of ERalpha and inhibits the binding of the estradiol-ER complex to the estrogen response element (ERE) in the DNA. The characteristics of melatonin's oncostatic actions, comprising different aspects of tumor biology as well as the physiological doses at which the effect is accomplished, give special value to these findings and encourage clinical studies on the possible therapeutic value of melatonin on breast cancer.
Jaesung (Peter) Choi, Yu Zheng, David J Handelsman, and Ulla Simanainen
Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n=8) and ugeARKO (n=7) uteri. Uterine weight was significantly (P=0.002) increased in ugePTENARKO (374±97 mg (mean±s.e.)) compared with WT (97±6 mg), ugeARKO (94±12 mg), and ugePTENKO (205±33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.
Rosalinda M Savoy and Paramita M Ghosh
Estrogens were once used for the treatment of prostate cancer (PC). They may still be used in various parts of the world to that effect. Recent developments in the understanding of a role for estrogen receptor β (ERβ) in the development and progression of this disease resurrect the discussion on the intertwined roles of ERβ and the androgen receptor (AR) in promoting PC. A new article by Zellweger et al. in Endocrine-Related Cancer investigates the expression and assesses the activity of ERα and ERβ as well as the AR, in addition to a phosphorylated form of AR in hormone-naïve and castration-resistant PC.