Entity

Time filter

Source Type

Cincinnati, OH, United States

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. Source


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. Source


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. Source


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. Source

Discover hidden collaborations