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Martinez A.M.,University of Cincinnati | Cheong A.,University of Cincinnati | Ying J.,University of Cincinnati | Xue J.,New York State Department of Health | And 8 more authors.
Biology of Reproduction | Year: 2015

Bisphenol A (BPA) is an endocrine disruptor associated with poor pregnancy outcomes in human and rodents. The effects of butterfat diets on embryo implantation and whether it modifies BPA's actions are currently unknown. We aimed to determine the effects of butterfat diet on embryo implantation success in female rats exposed to an environmentally relevant dose of BPA. Female Sprague-Dawley rats were exposed to dietary butterfat (10% or 39% kcal/kg body weight [BW]) in the presence or absence of BPA (250 μg/kg BW) or ethinylestradiol (0.1 μg/kg BW) shortly before and during pregnancy to assess embryo implantation potentials by preimplantation development and transport, in vitro blastulation, outgrowth, and implantation. On gestational day (GD) 4.5, rats treated with BPA alone had higher serum total BPA level (2.3-3.7 ng/ml). They had more late-stage preimplantation embryos, whereas those receiving high butterfat (HBF) diet had the most advanced-stage embryos; dams cotreated with HBF and BPA had the most number of advanced embryos. BPA markedly delayed embryo transport to the uterus, but neither amount of butterfat had modifying effects. An in vitro implantation assay showed HBF doubled the outgrowth area, with BPA having no effect. In vivo, BPA reduced the number of implanted embryos on GD8, and cotreatment with HBF eliminated this adverse effect. HBF diet overall resulted in more and larger GD8 embryos. This study reveals the implantation disruptive effects of maternal exposure to an environmentally relevant dose of BPA and identifies HBF diet as a modifier of BPA in promoting early embryonic health. ©2015 by the Society for the Study of Reproduction, Inc.


Cheong A.,University of Cincinnati | Zhang X.,University of Cincinnati | Cheung Y.-Y.,University of Cincinnati | Cheung Y.-Y.,Life Giving Foundation Education Center | And 12 more authors.
Epigenetics | Year: 2016

Developmental exposure to endocrine-disrupting chemicals (EDCs), 17β-estradiol-3-benzoate (EB) and bisphenol A (BPA), increases susceptibility to prostate cancer (PCa) in rodent models. Here, we used the methylated-CpG island recovery assay (MIRA)-assisted genomic tiling and CpG island arrays to identify treatment-associated methylome changes in the postnatal day (PND)90 dorsal prostate tissues of Sprague-Dawley rats neonatally (PND1, 3, and 5) treated with 25 µg/pup or 2,500 µg EB/kg body weight (BW) or 0.1 µg BPA/pup or 10 µg BPA/kg BW. We identified 111 EB-associated and 86 BPA-associated genes, with 20 in common, that have significant differentially methylated regions. Pathway analysis revealed cancer as the top common disease pathway. Bisulfite sequencing validated the differential methylation patterns observed by array analysis in 15 identified candidate genes. The methylation status of 7 (Pitx3, Wnt10b, Paqr4, Sox2, Chst14, Tpd52, Creb3l4) of these 15 genes exhibited an inverse correlation with gene expression in tissue samples. Cell-based assays, using 5-aza-cytidine-treated normal (NbE-1) and cancerous (AIT) rat prostate cells, added evidence of DNA methylation-mediated gene expression of 6 genes (exception: Paqr4). Functional connectivity of these genes was linked to embryonic stem cell pluripotency. Furthermore, clustering analyses using the dataset from The Cancer Genome Atlas revealed that expression of this set of 7 genes was associated with recurrence-free survival of PCa patients. In conclusion, our study reveals that gene-specific promoter methylation changes, resulting from early-life EDC exposure in the rat, may serve as predictive epigenetic biomarkers of PCa recurrence, and raises the possibility that such exposure may impact human disease. © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC © Ana Cheong, Xiang Zhang, Yuk-Yin Cheung, Wan-yee Tang, Jing Chen, Shu-Hua Ye, Mario Medvedovic, Yuet-Kin Leung, Gail S. Prins, and Shuk-Mei Ho.


News Article | November 17, 2016
Site: www.eurekalert.org

CINCINNATI--Researchers at the University of Cincinnati (UC) have discovered that an ion channel, active within T cells (white blood cells), could be targeted to reduce the growth of head and neck cancers. This research, which was reported this month in Cancer Research, shows that defective Kv1.3 channels, which regulate calcium ions (Ca2+) presence in T cells, and Ca2+ abnormalities in tumor infiltrating lymphocytes--cells that attack and kill cancer cells--may contribute to the inability of the immune system to fight off head and neck cancers. By regulating their expression at the cellular level and using the body's own immune response to fight the tumor cells, patients with these cancers could have better, more effective outcomes. "Head and neck squamous cell carcinoma is the sixth most common type of cancer, with a 5-year survival of 50 percent," says Laura Conforti, PhD, professor in the Department of Internal Medicine at the UC College of Medicine, a researcher within the UC Cancer Institute and corresponding author on the study. "The heterogeneity of these tumors, the complex anatomy of the head and neck region and the proximity of these tumors to several vital organs and structures present a challenge in conventional treatment options of these cancers. "Immunotherapies aimed to boost the immune system to fight cancer cells are showing promising results in this group of patients." Conforti says that to survive and spread, tumors create a cozy microenvironment where they often go unrecognized by the immune system. "The extent to which CD8+ cells, a type of T cell capable of killing cancer cells, infiltrate the head and neck tumor affects disease progression and responsiveness to therapy," she says. "Also, how well CD8+ lymphocytes function within the confines of the tumor microenvironment determines their ability to eradicate cancer cells, and in the case of head and neck solid tumors, tumor infiltrating lymphocytes have multiple functional defects, decreasing their ability to work correctly." "The function of CD8+ lymphocytes depends on Ca2+, which is controlled by ion channels. In particular, Kv1.3 ion channels regulate Ca2+ influx into T cells. In this study, we assessed the role of Kv1.3 channel and Ca2+ fluxes on these lymphocytes' function in head and neck cancer," she adds. Conforti says that her team, led by Ameet Chimote, PhD, research associate in the Division of Nephrology and Hypertension, used tumor samples and blood from 14 patients with head and neck cancers to analyze how Kv1.3 effected the function of tumor infiltrating T lymphocytes. They found a 70 percent reduction in functional Kv1.3 channels in tumor infiltrating lymphocytes as compared to the blood T cells, which was accompanied by a decrease in Ca2+ levels and reduced ability to attack and kill cancer cells. "Overall our data showed that suppression of Kv1.3 channels in these lymphocytes, the cells that fight off cancer, contribute to their decreased function, raising the possibility that this channel may be used as a potential marker of functionally competent T cells that have infiltrated the tumor mass," Conforti says. "These findings are particularly timely as a recently published study in Nature proposes these channels as potential new target for immunotherapy in cancer. The authors in this study reported that overexpressing these channels in an animal model with cancer lead to increased survival. "Further studies are needed on this T cell channel to find out more about its effects on head and neck cancer and ways we can target it to improve outcomes." This work was funded by grant support from the National Institutes of Health (Grant R01CA95286) and a pilot grant from the University of Cincinnati Cancer Institute and was done in collaboration with Trisha Wise-Draper, MD, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine, a member of both the Cincinnati Cancer Center and UC Cancer Institute, and Keith Casper, MD, a former UC faculty member who is now at the University of Michigan.


News Article | December 15, 2016
Site: www.cemag.us

Researchers at the University of Cincinnati (UC) College of Medicine have been able to generate multifunctional RNA nanoparticles that could overcome treatment resistance in breast cancer, potentially making existing treatments more effective in these patients. The study, published in the Dec. 14 online edition of American Chemical Society’s ACS Nano and led by Xiaoting Zhang, PhD, associate professor in the Department of Cancer Biology at the UC College of Medicine, shows that using a nanodelivery system to target HER2-positive breast cancer and stop production of the protein MED1 could slow tumor growth, stop cancer from spreading and sensitize the cancer cells to treatment with tamoxifen, a known therapy for estrogen-driven cancer. MED1 is a protein often produced at abnormally high levels in breast cancer cells that when eliminated is found to stop cancer cell growth. HER2-positive breast cancer involves amplification of a gene encoding, or programming, the protein known as human epidermal growth factor receptor 2, which also promotes the growth of cancer cells. MED1 co-produces (co-expresses) and co-amplifies with HER2 in most cases, and Zhang’s previous studies have shown their interaction plays key roles in anti-estrogen treatment resistance. "Most breast cancers express estrogen receptors, and the anti-estrogen drug tamoxifen has been widely used for their treatment,” says Zhang, who is also a member of the Cincinnati Cancer Center and the UC Cancer Institute. "Unfortunately, up to half of all estrogen receptor-positive tumors are either unresponsive or later develop resistance to the therapy. In this study, we have developed a highly innovative design that takes advantage of the co-overexpression of HER2 and MED1 in these tumors.” Zhang and researchers in his lab found that these RNA nanoparticles were able to selectively bind to HER2-overexpressing breast tumors, eliminating MED1 expression and significantly decreasing estrogen receptor-controlled target gene production. The RNA nanoparticles not only reduced the growth and spread of the HER2-overexpressing breast cancer tumors, but also sensitized them to tamoxifen treatment. "These bio-safe nanoparticles efficiently targeted and penetrated into HER2-overexpressing tumors after administration in animal models,” he says. "In addition, these nanoparticles also led to a dramatic reduction in the cancer stem cell content of breast tumors when combined with tamoxifen treatment. Cancer stem cells, as you know, are tumor-causing cells that are known to play essential roles in tumor spread, recurrence and therapy resistance. Eliminating these cells could represent an improved and more desirable treatment strategy for breast cancer patients. "These findings are highly promising for potential clinical treatment of advanced metastatic and tamoxifen-resistant human breast cancer. Further studies are still needed and hopefully soon we’ll be able to test our nanoparticles in clinical trials at the UC Cancer Institute’s Comprehensive Breast Cancer Center.” Along with Zhang, the first author of the study is Yijuan Zhang, PhD, with co-authors Marissa Leonard and Yongguang Yang, PhD from his lab at UC. Other collaborators include Ohio State University researchers Dan Shu, PhD, and Yi Shu, PhD, in the laboratory of RNA nanotechnology expert Peixuan Guo, PhD. This study was supported by the UC Cancer Institute Drake Pilot Award, Ride Cincinnati, a Cincinnati Cancer Center Pilot Grant, the Susan G. Komen Career Catalyst Research Grant (KG110028), the National Institutes of Health (R01CA197865, R01 EB019036) and the U.S. Department of Defense Idea Award (W81XWH-15-1-0052). Zhang cites no conflict of interest; however, Guo is the cofounder of Biomotor and RNA Nanotechnology Development Corp. Ltd.


News Article | December 14, 2016
Site: www.eurekalert.org

CINCINNATI--Researchers at the University of Cincinnati (UC) College of Medicine have been able to generate multifunctional RNA nanoparticles that could overcome treatment resistance in breast cancer, potentially making existing treatments more effective in these patients. The study, published in the Dec. 14, 2016, online edition of American Chemical Society's ACS Nano and led by Xiaoting Zhang, PhD, associate professor in the Department of Cancer Biology at the UC College of Medicine, shows that using a nanodelivery system to target HER2-positive breast cancer and stop production of the protein MED1 could slow tumor growth, stop cancer from spreading and sensitize the cancer cells to treatment with tamoxifen, a known therapy for estrogen-driven cancer. MED1 is a protein often produced at abnormally high levels in breast cancer cells that when eliminated is found to stop cancer cell growth. HER2-positive breast cancer involves amplification of a gene encoding, or programming, the protein known as human epidermal growth factor receptor 2, which also promotes the growth of cancer cells. MED1 co-produces (co-expresses) and co-amplifies with HER2 in most cases, and Zhang's previous studies have shown their interaction plays key roles in anti-estrogen treatment resistance. "Most breast cancers express estrogen receptors, and the anti-estrogen drug tamoxifen has been widely used for their treatment," says Zhang, who is also a member of the Cincinnati Cancer Center and the UC Cancer Institute. "Unfortunately, up to half of all estrogen receptor-positive tumors are either unresponsive or later develop resistance to the therapy. In this study, we have developed a highly innovative design that takes advantage of the co-overexpression of HER2 and MED1 in these tumors." Zhang and researchers in his lab found that these RNA nanoparticles were able to selectively bind to HER2-overexpressing breast tumors, eliminating MED1 expression and significantly decreasing estrogen receptor-controlled target gene production. The RNA nanoparticles not only reduced the growth and spread of the HER2-overexpressing breast cancer tumors, but also sensitized them to tamoxifen treatment. "These bio-safe nanoparticles efficiently targeted and penetrated into HER2-overexpressing tumors after administration in animal models," he says. "In addition, these nanoparticles also led to a dramatic reduction in the cancer stem cell content of breast tumors when combined with tamoxifen treatment. Cancer stem cells, as you know, are tumor-causing cells that are known to play essential roles in tumor spread, recurrence and therapy resistance. Eliminating these cells could represent an improved and more desirable treatment strategy for breast cancer patients. "These findings are highly promising for potential clinical treatment of advanced metastatic and tamoxifen-resistant human breast cancer. Further studies are still needed and hopefully soon we'll be able to test our nanoparticles in clinical trials at the UC Cancer Institute's Comprehensive Breast Cancer Center." Along with Zhang, the first author of this study is Yijuan Zhang, PhD, with co-authors Marissa Leonard and Yongguang Yang, PhD from his lab at UC. Other collaborators include Ohio State University researchers Dan Shu, PhD, and Yi Shu, PhD, in the laboratory of RNA nanotechnology expert Peixuan Guo, PhD. This study was supported by the UC Cancer Institute Drake Pilot Award, Ride Cincinnati, a Cincinnati Cancer Center Pilot Grant, the Susan G. Komen Career Catalyst Research Grant (KG110028), the National Institutes of Health (R01CA197865, R01 EB019036) and the U.S. Department of Defense Idea Award (W81XWH-15-1-0052). Zhang cites no conflict of interest; however, Guo is the cofounder of Biomotor and RNA Nanotechnology Development Corp. Ltd.


The study, published in the Dec. 14, 2016, online edition of American Chemical Society's ACS Nano and led by Xiaoting Zhang, PhD, associate professor in the Department of Cancer Biology at the UC College of Medicine, shows that using a nanodelivery system to target HER2-positive breast cancer and stop production of the protein MED1 could slow tumor growth, stop cancer from spreading and sensitize the cancer cells to treatment with tamoxifen, a known therapy for estrogen-driven cancer. MED1 is a protein often produced at abnormally high levels in breast cancer cells that when eliminated is found to stop cancer cell growth. HER2-positive breast cancer involves amplification of a gene encoding, or programming, the protein known as human epidermal growth factor receptor 2, which also promotes the growth of cancer cells. MED1 co-produces (co-expresses) and co-amplifies with HER2 in most cases, and Zhang's previous studies have shown their interaction plays key roles in anti-estrogen treatment resistance. "Most breast cancers express estrogen receptors, and the anti-estrogen drug tamoxifen has been widely used for their treatment," says Zhang, who is also a member of the Cincinnati Cancer Center and the UC Cancer Institute. "Unfortunately, up to half of all estrogen receptor-positive tumors are either unresponsive or later develop resistance to the therapy. In this study, we have developed a highly innovative design that takes advantage of the co-overexpression of HER2 and MED1 in these tumors." Zhang and researchers in his lab found that these RNA nanoparticles were able to selectively bind to HER2-overexpressing breast tumors, eliminating MED1 expression and significantly decreasing estrogen receptor-controlled target gene production. The RNA nanoparticles not only reduced the growth and spread of the HER2-overexpressing breast cancer tumors, but also sensitized them to tamoxifen treatment. "These bio-safe nanoparticles efficiently targeted and penetrated into HER2-overexpressing tumors after administration in animal models," he says. "In addition, these nanoparticles also led to a dramatic reduction in the cancer stem cell content of breast tumors when combined with tamoxifen treatment. Cancer stem cells, as you know, are tumor-causing cells that are known to play essential roles in tumor spread, recurrence and therapy resistance. Eliminating these cells could represent an improved and more desirable treatment strategy for breast cancer patients. "These findings are highly promising for potential clinical treatment of advanced metastatic and tamoxifen-resistant human breast cancer. Further studies are still needed and hopefully soon we'll be able to test our nanoparticles in clinical trials at the UC Cancer Institute's Comprehensive Breast Cancer Center." Explore further: New finding gives clues for overcoming tamoxifen-resistant breast cancer More information: Yijuan Zhang et al. Overcoming Tamoxifen Resistance of Human Breast Cancer by Targeted Gene Silencing using Multifunctional pRNA Nanoparticles, ACS Nano (2016). DOI: 10.1021/acsnano.6b05910


Govindarajah V.,University of Cincinnati | Leung Y.-K.,University of Cincinnati | Leung Y.-K.,Cincinnati Cancer Center | Ying J.,University of Cincinnati | And 6 more authors.
Journal of Nutritional Biochemistry | Year: 2016

Human studies suggest that high-fat diets (HFDs) increase the risk of breast cancer. The 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis rat model is commonly used to evaluate the effects of lifestyle factors such as HFD on mammary tumor risk. Past studies focused primarily on the effects of continuous maternal exposure on the risk of offspring at the end of puberty (PND50). We assessed the effects of prenatal HFD exposure on cancer susceptibility in prepubertal mammary glands and identified key gene networks associated with such disruption. During pregnancy, dams were fed AIN-93G-based diets with isocaloric high olive oil, butterfat or safflower oil. The control group received AIN-93G. Female offspring were treated with DMBA on PND21. However, a significant increase in tumor volume and a trend of shortened tumor latency were observed in rats with HFD exposure against the controls (P=.048 and P=.067, respectively). Large-volume tumors harbored carcinoma in situ. Transcriptome profiling identified 43 differentially expressed genes in the mammary glands of the HFBUTTER group as compared with control. Rapid hormone signaling was the most dysregulated pathway. The diet also induced aberrant expression of Dnmt3a, Mbd1 and Mbd3, consistent with potential epigenetic disruption. Collectively, these findings provide the first evidence supporting susceptibility of prepubertal mammary glands to DMBA-induced tumorigenesis that can be modulated by dietary fat that involves aberrant gene expression and likely epigenetic dysregulation. © 2015 Elsevier Inc.


Lam H.-M.,University of Cincinnati | Lam H.-M.,University of Washington | Ouyang B.,University of Cincinnati | Chen J.,University of Cincinnati | And 10 more authors.
Endocrine-Related Cancer | Year: 2014

Castration-resistant prostate cancer (CRPC) is an advanced-stage prostate cancer (PC) associated with high mortality. We reported that G-1, a selective agonist of G proteincoupled receptor 30 (GPR30), inhibited PC cell growth by inducing G2 cell cycle arrest and arrested PC-3 xenograft growth. However, the therapeutic actions of G-1 and their relationships with androgen in vivo are unclear. Using the LNCaP xenograft to model PC growth during the androgen-sensitive (AS) versus the castration-resistant (CR) phase, we found that G-1 inhibited growth of CR but not AS tumors with no observable toxicity to the host. Substantial necrosis (approximately 65%) accompanied by marked intratumoral infiltration of neutrophils was observed only in CR tumors. Global transcriptome profiling of human genes identified 99 differentially expressed genes with 'interplay between innate and adaptive immune responses' as the top pathway. Quantitative PCR confirmed upregulation of neutrophil-related chemokines and inflammation-mediated cytokines only in the G-1-treated CR tumors. Expression of murine neutrophil-related cytokines also was elevated in these tumors. GPR30 (GPER1) expression was significantly higher in CR tumors than in AS tumors. In cell-based experiments, androgen repressed GPR30 expression, a response reversible by anti-androgen or siRNA-induced androgen receptor silencing. Finally, in clinical specimens, 80% of CRPC metastases (n=123) expressed a high level of GPR30, whereas only 54% of the primary PCs (n=232) showed high GPR30 expression. Together, these results provide the first evidence, to our knowledge that GPR30 is an androgen-repressed target and G-1 mediates the anti-tumor effect via neutrophil-infiltration-associated necrosis in CRPC. Additional studies are warranted to firmly establish GPR30 as a therapeutic target in CRPC. © 2014 Society for Endocrinology Printed in Great Britain.


Yang S.,University of Cincinnati | Pinney S.M.,University of Cincinnati | Pinney S.M.,Cincinnati Cancer Center | Mallick P.,University of Cincinnati | And 5 more authors.
Clinical Genitourinary Cancer | Year: 2015

Objective: Biomarkers of oxidative stress and advanced glycation end products (AGE) have been linked to the development of prostate cancer, but evidence from human studies is scarce or controversial. Methods: We conducted a prospective nested case-control study among 48 men (24 prostate cancer cases and 24 controls) aged 48 to 76 years at baseline. The participants of our study were a part of the Fernald Community Cohort. Prostate cancer cases and controls were matched individually on age (± 3 years) with a 1:1 ratio. Biomarkers included urine F2-isoprostanes (markers of lipid oxidation), plasma fluorescent oxidation products (markers of global oxidation), and carboxymethyllysine (CML) (a major end-stage AGE). Results: At baseline, cases had similar age, body mass index, proportion of family history of prostate cancer, history of benign prostatic hyperplasia, history of hypertension, history of diabetes, number of smokers, and plasma glucose levels compared with controls. Levels of plasma CML were significantly higher in cases than in controls (182 vs. 152 μg/mL, P <.05). In the conditional logistic regression model, an increase in CML equivalent to 1 standard deviation was associated with an increased risk of incident prostate cancer (relative risk, 1.79; 95% confidence interval, 1.00-3.21) and accounted for approximately 8% variance of prostate cancer liability. Urine F2-isoprostanes and plasma fluorescent oxidation products were not associated with prostate cancer incidence. Conclusions: Higher levels of plasma CML were associated with increased risk of prostate cancer. This suggests a potential new pathway for prostate cancer prediction and treatment. © 2015 Elsevier Inc. All rights reserved.

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