bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B90: Doses of selective estrogen receptor modulations (SERMs) required for prevention and therapy of chemically induced mammary cancers
Authors: Heckman-Stoddard Brandy M. , Grubbs Clinton , Lubet Ronald 
Published: May 2012

Abstract
Selective Estrogen Receptor Modulators (SERMs) interfere with the activity of estrogen. SERMs have been shown to be effective for both treatment and prevention of breast cancer. Here we examine the ability of Tamoxifen and Arzoxifene, a more easily absorbed form of Raloxifene, to prevent mammary tumors at a significantly lower dosage than those used for treatment. For prevention studies, treatment of female Sprague-Dawley rats (50 days of age) with a single dose of MNU resulted in the development of multiple ER-positive mammary tumors beginning 7 weeks after carcinogen treatment. When examined in a chemoprevention setting, rats were administered the preventive agent beginning five days after carcinogen administration. When the agents were tested at does varying between 0.15–3.3 ppm in the diet, both agents caused a dose dependent increase in preventive activity. The highest doses of tamoxifen (3.3 ppm) and Arzoxifene (3.0 ppm) both decreased tumor multiplicity greater than 90%. Both of these doses are less than one-fifth the human equivalent dose (HED) based on standard FDA scaling factors. Both doses also resulted in substantial decreases in mammary gland development. These dosages were then used in a therapy setting to compare the efficacy. For these studies, MNU treated rats were allowed to develop their first palpable mammary tumor (70–150 mm2) before initiating treatment. Tumor growth or regression was followed by caliper measurements. Neither of the higher preventive doses of these SERMs exhibited substantial therapeutic activity, although substantially higher doses of tamoxifen (33 or 100 ppm) were relatively effective. These results are in contrast to our prior findings with other classes of agents (RXR agonists, EGFR inhibitors, and aromatase inhibitors) in which highly effective preventive doses were effective as the therapeutic doses in this model. These results demonstrate the unique dose differential regarding prevention and therapy with SERMs. It raises the question of whether this class of agents might be used at significantly lower doses in a pure prevention setting.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B90.
Abstract B91: Induction of RXR transcriptional activity and consequent upregulation of p21 by 3-amino-6-(3-aminopropyl)-5,6-dihydro-5, 11-dioxo-11H-indeno[1,2-c]isoquinoline dihydrochloride in MCF-7 breast cancer cells
Authors: Park Eun-Jung , Kondratyuk Tamara , Morrell Andrew , Kiselev Evgeny , Cushman Mark , Pezzuto John 
Published: May 2012

Abstract
Retinoid X receptor (RXR) is known to play various roles in embryogenesis, metabolic processes, differentiation, and apoptosis. Recently, RXR has been studied as a target for cancer chemoprevention and treatment. To discover potential cancer chemopreventive agents acting through RXRs, we developed a cell line-based RXR response element (RXRE)-luciferase reporter gene assay system. Following extensive screening, 3-amino-6-(3aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline dihydrochloride (AM6-36) was found to induce RXRE-luciferase activities in a dose-dependent manner. Subsequently, the substance was found to inhibit the proliferation of MCF-7 breast cancer cells in a concentration-dependent manner. Prompted by these results, we examined the underlying mechanism of AM6-36 anti-proliferative activity using MCF-cells as a model. In brief, at lower concentrations, G2/M arrest was observed, and S phase arrest was enhanced at higher concentrations. Based on DNA microarray analysis, AM6-36 was found to up-regulate the expression of CDKN1A, a target gene of RXR, by ∼40-fold. In accordance with this response, the protein level of CDKN1A (p21WAF1/CIP1) was increased in the presence of AM6-36. Induction of p21 by AM6-36 was abrogated following transient transfection of RXR siRNA, demonstrating the effect of AM6-36 on the expression of p21 is closely related to modulation of RXR transcriptional activity. These data suggest AM6-36 is a promising lead compound for the treatment or prevention of breast cancer. A synthetic procedure has been devised for large-scale production, moderate absorption and slow metabolism has been demonstrated with rats (p.o. administration), and more advanced anti-tumor evaluation is underway. (Supported by program project P01 CA48112 awarded by the National Cancer Institute.)
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B91.
Abstract B92: Combating prostate cancer by targeting androgen receptor with phytochemical resveratrol
Authors: Zhang Dianzheng 
Published: May 2012

Abstract
The chemopreventive effects of resveratrol (RSV) on prostate cancer have been well established; the androgen receptor (AR) plays pivotal roles in prostatic tumorigenesis. However, the exact underlying molecular mechanisms about the effects of RSV on AR have not been fully elucidated. A model system is needed to determine whether and how RSV represses AR transcriptional activity. The AR cDNA was first cloned into the retroviral vector pOZ-N and then integrated into the genome of AR-negative HeLa cells to generate the AR(+) cells. The constitutively expressed AR was characterized by monitoring hormone-stimulated nuclear translocation, DNA binding, and transcriptional activation, with the AR(−) cells serving as controls. AR(+) cells were treated with RSV, and both AR protein levels and AR transcriptional activity were measured simultaneously. Chromatin immunoprecipitation (ChIP) assays were used to detect the effects of RSV on the recruitment of AR to its cognate element (ARE). AR in the AR (+) stable cell line functions in a manner similar to that of endogenously expressed AR. Using this model system we clearly demonstrated that RSV represses AR transcriptional activity independently of any effects on AR protein levels. However, neither the hormone-mediated nucleus translocation nor the AR/ARE interaction was affected by RSV treatment. We demonstrated unambiguously that RSV regulates AR target gene expression, at least in part, by repressing AR transcriptional activity. Repressive effects of RSV on AR activity result from mechanisms other than the affects of AR nuclear translocation or DNA binding.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B92.
Abstract B93: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may decrease cancer-related mortality in patients with small-cell lung cancer
Authors: Arnaout Karim , Farhan Shatha , Rana Jatin , Jankowski Michelle , Wang Ding 
Published: May 2012

Abstract
Introduction: Small-cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival at five years for patients with SCLC is estimated to be five to ten percent. Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) have been reported to decrease the risk of lung cancer. The aim of this retrospective study was to investigate the association between ACE inhibitors and ARBs and cancerrelated mortality in patients with SCLC.
Methods: In this study, we retrospectively reviewed the charts of 360 patients diagnosed with SCLC in our institution between 1995 and 2004. 199 patients with advanced SCLC, deceased at the time of this report, and for whom the cause of death was known, were identified. Within this group, cancer-related mortality in patients who were on ACE inhibitors and/or ARBs was compared to that of patients not on these medications.
Results: Out of 199 patients, 58 (29%) were on ACE inhibitors and/or ARBs, 141 (71%) were not. In ACE inhibitor and/or ARB users, cancer was the cause of death in 34 patients. In patients not on ACE inhibitors and/or ARBs, 103 died from cancer. Patients on ACE inhibitors and/or ARBs had a 14% decrease in cancer-related mortality compared to patients who were not on these medications (59% versus 73% respectively, P= 0.046).
Conclusion: Our data support the fact that ACE inhibitors and ARBs may be associated with a decrease in cancer-related mortality in patients with SCLC. This could be related to their inhibitory effects on angiogenesis and tumor growth, by blocking angiotensin II and increasing the levels of angiotensin (1–7). However, prospective studies are needed to establish the effect of ACE inhibitors and ARBs on cancer-related mortality in patients with SCLC.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B93.
Abstract B96: Phylogenetic relatedness and novel mutations in the whole genomes of genotype A (subgenotype A1) of HBV isolates from a north Indian population
Authors: Singh Jasbir , Pahal Vikas , Kumar Rajesh 
Published: May 2012

Abstract
Hepatitis B virus (HBV) has been classified into eight genotypes (A to H). The predominant genotypes in India are genotype D followed by genotype A and C. Our laboratory has first time reported genotypes E and F in India. In the present study, whole genome (approximately 3.2 kb long) was amplified from five chronic HBV patients, who are HBeAg negative and having nearly normal ALT/AST levels. The samples were sequenced to complete length and sequences were compared to wild type sequences from database. Phylogenetic analysis shows high degree of closeness of our strains with Philippines and eastern Indian strains. Our study confirmed 33–35 point mutations out of already reported 38 subgenotype A1 specific point mutations and which are distributed throughout the genome including enhancer I–X promoter, enhancer II-Core promoter, encapsidation signal, S1 and S2 promoter regions etc. In addition to this, novel Kozak sequence mutations like CCTT at positions 1809/10/11/1812 in place of regular TCAT sequence were also observed. This region comprises the Enhancer II-Core promoter region and mutations of this region results in decreased production of HBeAg. 1041G was present in place of 1041T in Enhancer I–X promoter region. It has been observed that Genotype A has G1896A mutation when preceded by a C1858T mutation, thus conserving the structural stability of the encapsidation signal. One sample shows the presence of 1858T with 1896G mutation, which results in weakness of structural stability of encapsidation signal. In addition, our samples show presence of 1862T which is a missense mutation and responsible for val to leu/phe amino acid substitution. This mutation is responsible for low production of HBeAg protein and found mainly in HBeAg negative patient. Samples also showed the deletion at 19 novel sites and addition at 5 novel sites when compared with the whole genome from database. The significance of these deletion and addition mutations and their effects on the disease progression to hepatocellularcarcinoma is active area of research in our laboratory.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B96.
Abstract B97: Alcoholic beverages and prostate cancer in a prospective U.S. cohort study
Authors: Watters Joanne , Park Yikyung , Hollenbeck Albert , Schatzkin Arthur , Albanes Demetrius 
Published: May 2012

Abstract
Higher alcohol consumption has been shown to be a risk factor for many cancers, yet despite a number of investigations, its relation to prostate cancer has not been established. We investigated the association between alcohol consumption and risk of prostate cancer in a large prospective study of dietary and environmental cancer risk factors among 294,707 men aged 50–71 years old upon enrollment in 1995–1996. Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (95% CI) were adjusted for several characteristics including age, race, body mass index, physical activity, family history of prostate cancer, and PSA and DRE testing. There were 15,327 nonadvanced and 1,900 advanced incident prostate cancers identified through 2003 and 514 men died of prostate cancer through 2005. Risk of nonadvanced prostate cancer was 25% higher in men consuming 6 or more drinks per day (HR= 1.25, 95% CI: 1.13 – 1.37), 19% higher in men consuming between 3 and 6 drinks per day (HR= 1.19, 95% CI: 1.11 – 1.29), and 6% higher in men consuming up to 3 drinks per day compared to nondrinkers (HR= 1.06, 95% CI: 1.00 – 1.12). The lowest risk of nonadvanced prostate cancer was seen among nondrinkers. We observed no association between alcohol intake and advanced cancers and a possible association against fatal prostate cancer among a small number of heavy drinkers with 6+ drinks daily (HR= 0.45, 95% CI: 0.25 – 0.81). There were similar associations observed for all types of alcoholic beverages (i.e., wine, beer, liquor). In this large prospective study, we found that alcohol consumption modestly increased the risk of nonadvanced prostate cancers.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B97.
Abstract B98: Dietary fiber is associated with circulating concentrations of inflammatory markers among breast cancer survivors
Authors: Villaseñor Adriana , Ambs Anita , Ballard-Barbash Rachel , Baumgartner Kathy B. , Coronado Gloria , McTiernan Anne , Ulrich Cornelia M. , Neuhouser Marian L. 
Published: May 2012

Abstract
Introduction: An association between high intake of dietary fiber and low circulating concentrations of inflammatory markers has been suggested by previous research. However, epidemiological data from cohort studies of breast cancer survivors are sparse.
Methods: We examined associations between dietary fiber and serum concentrations of CRP and SAA, among 698 female breast cancer survivors from the Health, Eating, Activity, and Lifestyle (HEAL) Study. Data are from an interview conducted 24 months after study enrollment. Multivariate-adjusted linear regression estimated the association of total, soluble and insoluble fiber with serum concentrations of CRP and SAA. Logistic regression estimated the odds of elevated CRP (defined as &gt;3.0 mg/L) across tertiles of fiber intake.
Results: Mean total dietary fiber intake was 13.96 ± 6.38 gm/day. Mean CRP and SAA were 3.32 ± 3.66 mg/L and 7.73 ± 10.23 mg/L, respectively. After controlling for potential confounders, including age, body mass index (BMI), smoking, physical activity, total caloric intake, alcohol consumption, fat intake, postmenopausal status, inflammatory-related diseases, medication use, disease stage and adjuvant treatment, we observed an inverse association between intake of total dietary fiber intake and CRP concentrations (β, −0.029; 95% CI, −0.049, −0.008). SAA was not associated with fiber intake (β, −0.002; 95% CI, −0.016, 0.012). Among the various fiber fractions of dietary fiber, only insoluble fiber was inversely associated with circulating concentrations of CRP (β, −0.039; 95% CI, −0.064, −0.013). The likelihood of elevated CRP concentrations was lower (OR, 0.57; 95% CI, 0.30, 1.07) among participants who consumed &gt;16 g/day total dietary fiber compared with consumption of 15.5 g/day of insoluble dietary fiber compared to those who reported &lt;5.4 g/day with moderate significance (p = 0.053).
Conclusion: Our results suggest that diets high in fiber may be of benefit to breast cancer survivors due to fiber's correlation with lower circulating concentrations of CRP, recently shown to affect breast cancer survival.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B98.
Abstract CN04-03: Esophageal cancer and the tumor microenvironment
Authors: Rustgi Anil K. , Stairs Douglas B. , Grugan Katharine D. , Wong Gabrielle S. , Vega Maria E. , Kalabis Jiri , Nakagawa Hiroshi , Gimotty Phyllis A. , Klein-Szanto Andres J. , Diehl J.Alan , Herlyn Meenhard 
Published: May 2012

Abstract
Squamous cell cancers are the most common type of epithelially derived human cancers and arise from a number of diverse sites. They share a number of common genetic alterations and environmental exposures. Employing oral and esophageal cancers as prototypes, we have developed three-dimensional (3D) or organoptypic models that represent a form of human tissue engineering (Genes and Development 2007; Journal of Clinical Investigation 2008). These approaches underscore the combinatorial roles of EGFR signaling and p53 mutation in fostering tumor cell migration and invasion in the microenvironment. Microarray analyses reveal specific effectors in the adhesion family of genes that might be exploited as biomarkers for detection and targets for new therapeutics. We have also generated genetically engineered mouse models that reveal the effects of cyclin D1 overexpression in concert with p53 loss, as well as the role of p120-catenin loss in the initiation and progression of cancer.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN04-03.
Abstract CN05-02: Energy balance and cancer at the bench: What's new?
Authors: Thompson Henry J. 
Published: May 2012

Abstract
Evidence is strong that a reduction in risk for certain types of cancer is associated with moderate to vigorous physical activity (PA); however, there is limited understanding of the role of type, intensity, duration, and frequency of PA and their mechanisms in accounting for this health benefit. The objective of this presentation is to provide insights from preclinical investigations of PA and breast cancer that inform the general understanding of candidate mechanisms that may account for both the energy dependent and independent effects of PA. Hypotheses about cellular mechanisms will be linked to hypotheses to about systemic effects of PA. Issues considered will include: 1) what contracting muscle releases into circulation or removes from circulation that would directly modulate the carcinogenic process in epithelial cells; 2) whether the effects of muscle contraction on epithelial cell carcinogenesis are exerted in an endocrine, paracrine, autocrine, or intracrine manner; and 3) if the effects of muscle contraction on malignant cells differ from effects on normal or premalignant cells that do not manifest the hallmarks of malignancy.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN05-02.
Abstract CN07-03: Polymorphisms in miRNA binding sites as risk factors for cancer development
Authors: Weidhaas Joanne B. 
Published: May 2012

Abstract
Purpose: Ovarian cancer is the single most deadly form of cancer specific to women, largely due to a lack of known risk factors or genetic markers. The KRAS oncogene and altered levels of the microRNA let-7 are associated with increased risk of developing solid tumors, such as ovarian cancer. We investigated a single nucleotide variant (rs61764370) that disrupts a let-7 microRNA binding site in the KRAS oncogene as a biomarker of ovarian cancer risk.
Methods: Specimens were obtained from non-selected ovarian cancer patients in three independent cohorts (n = 445) and two independent ovarian case-control studies. Specimens from ovarian cancer patients with hereditary breast and ovarian cancer (HBOC) syndrome (n = 52) and their family members were also collected.
Results: rs61764370 is in greater than 30% of non-selected ovarian cancer cases and is a marker for a significant increased risk of developing ovarian cancer by case control analysis (n = 201, OR = 2.46, CI = 1.14–5.29, p = .020). This was validated in a second independent ovarian case-control (n = 648). Furthermore, rs61764370 was identified in 58% of HBOC patients without BRCA1 or BRCA2 mutations (n = 24, p &lt; 0.001), therefore previously considered uninformative, as well as in their family members with cancer.
Conclusions: These findings support the hypothesis that rs61764370 is a genetic marker of increased risk of developing ovarian cancer, and suggests that rs61764370 may be a new biomarker of risk for HBOC families without other known genetic abnormalities.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN07-03.
Abstract CN07-04: RNAi in the treatment and epigenetics of cancer
Authors: Rossi John J. , Sun Guiha , Kim Daniel 
Published: May 2012

Abstract
RNA interference is a broad term used to describe several different mechanisms for regulation of gene expression mediated by small RNAs. Small interfering RNAs (siRNAs) trigger sequence specific cleavage of mRNAs via fully complementary base pairing, resulting in cleavage and subsequent total degradation of the targeted transcript. Micro RNAs (miRNAs) are the guides for triggering translational inhibition of gene expression via partially complementary pairing to the 3′ UTRs of target transcripts. Small RNAs can also modulate gene expression via directing chromatin remodeling, resulting in heterochromatin formation and silencing of transcription. Each of these mechanisms has important implications for the prevention and diagnosis of cancer. SiRNAs are not commonly found in mammalian cells, but may be present during gametogenesis to control retroposon movement. The functional consequences of aberrations in the production and functioning of siRNAs could lead to genomic rearrangements and other chromosome abnormalities. MiRNAs have been shown to be important micro-managers of gene expression, and a single miRNA can repress translation of upwards of two hundred different proteins. MiRNA profiling has shown that aberrant expression of these micro-managers can be diagnostic and prognostic for several different cancers. Given the importance of miRNAs in controlling cell fates and ultimately progression to cancer, it is important to understand what types of aberrations can affect their function. Micro RNAs are produced via a two step processing reaction involving two different RNAse III family members (Drosha and Dicer) and their cofactors. Perturbations of either of these processing steps can alter the amount and even the final processed sequence of miRNAs. The first part of this presentation will focus on naturally occurring point mutations identified in X-linked miRNA genes and the consequences of these mutations on miRNA function. Point mutations in miRNA precursors as well as mature sequences can lead to altered miRNA function and could have a profound effect on regulation of the translation of both targeted and non-targeted mRNAs.
Small RNAs that can modulate chromatin structure also present a possible tool for cancer prevention. Two examples of small RNAs modulating chromatin structure will be presented. The first example is the use of promoter targeting siRNAs to silence an important tumor suppressor, RASFF1A. The second example illustrates how an endogenous microRNA targeting a promoter region can modulate expression of an essential RNA Polymerase 3 subunit.
The last part of this presentation will focus on some strategies for delivering siRNAs or miRNAs in a targeted fashion to modulate expression of genes. These strategies could be useful in cancer prevention and as cancer treatments.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):CN07-04.