bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3299: Bacterial DNA integrations in the genomes of gastric tumor and adjacent samples
Authors: Robinson Kelly , Kumar Nikhil , Torres Javier , Dunning Hotopp Julie C. 
Published: July 2016

Abstract
There are 10 times more bacterial cells in the human body than human cells, and various bacteria are known to influence carcinogenesis. While viral DNA integrations in the human genome have been shown to promote carcinogenesis, bacterial DNA integrations (BDI) into the human genome are rarely investigated. Our previous analysis of publicly available sequencing data from the Cancer Genome Atlas showed BDIs from Pseudomonas spp. rRNA into the 5’-UTR of four proto-oncogenes as well as in Ig (the immunoglobulin gene) of gastric cancer samples. However, we were left with many unanswered questions when we were unable to obtain the materials required to validate our findings. Therefore, we sought to sequence a different cohort of gastric cancer patients in order to identify BDIs. Whole exome sequencing was completed on seven tumor samples and six adjacent gastric samples, as well as one intestinal metaplasia sample and one non-atrophic gastritis sample. Four of those samples were also investigated with transcriptomics and whole genome sequencing. Using our previously published BWA-based pipeline, we identified putative BDIs from Helicobacter pylori rRNA into numerous genes in one tumor sample as well as in its adjacent matched sample, including BDIs in the Ig locus. Helicobacter pylori is considered a carcinogen by the World Health Organization due to its ability to promote carcinogenesis in gastric tissue, causing us to speculate that these integrations could be carcinogenic. Similarly to our analysis of the Cancer Genome Atlas data, we also identified a few samples with BDIs from Pseudomonas spp. and about half of the samples possessed BDIs from other bacteria. We identified at least one BDI in each sample regardless of the sequencing data type. Validation of these results is ongoing and will be presented. Given these results, more consideration should be given to BDIs into the human genome when bacterial associations with diseases are suspected.
Citation Format: Kelly Robinson, Nikhil Kumar, Javier Torres, Julie C. Dunning Hotopp. Bacterial DNA integrations in the genomes of gastric tumor and adjacent samples. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3299.
Abstract 3308: Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice
Authors: Bouamar Hakim , Zhang Fuchuang , Gu Xiang , Dong Qiaoxiang , Sun Lu-Zhe 
Published: July 2016

Abstract
Breast cancer is a commonly diagnosed cancer during pregnancy. However, how endogenous and exogenous endocrine factors may contribute to the development of pregnancy-associated mammary tumorigenesis is not clear. There is growing evidence that mammary stem cells (MaSCs) may initiate neoplastic transformation when dysregulated in mouse models. We investigated the effect of the environmental endocrine disruptor bisphenol A (BPA) on mouse mammary gland morphology, epithelial cell composition, pre-neoplastic lesions, and the regenerative function of MaSCs. Pregnant FVB mice with GFP transgene on Day E8.5 were implanted with osmotic pumps that constantly release BPA at 0, 25 or 250 ng/kg/day for 28 days and the mice were euthanized one month after weaning. In agreement with the literature, we observed an abnormality of the morphology of the mammary gland after BPA treatment characterized by higher duct density and abnormal secondary and tertiary branching. Quantification of percent hyperplastic mammary ducts in H&E-stained tissue slides revealed a significant increase of ducts with hyperplastic lesions after BPA treatment, particularly with the low dose. To investigate the effects of BPA treatment on MaSCs, we used enzyme digestion to isolate the CD24hi/CD49f+ luminal epithelial cells (also termed as colony forming cell or CFC) and the CD24+/CD49fhi basal epithelial cells (also termed as mammary repopulating unit or MRU) from mammary gland tissues by FACS and found no significant difference in percent of luminal or basal cell population after BPA treatment. Because the basal cells are enriched with MaSCs that can form mammospheres in suspension culture and subsequently form solid 3D organoids when cultured in Matrigel, we transplanted the solid 3D organoids into cleared mammary fat pads of syngeneic FVB mice and immune-compromised nude mice to examine how BPA treatment might alter MaSC function. Significantly, similar to the results from the primary mammary glands, the regenerated mammary glands by MaSCs from mice treated with the low dose of BPA showed increased duct density, secondary and tertiary branching, and a significantly greater number of hyperplastic lesions. Taken together, our study demonstrated that BPA exposure at very low dose could induce pre-neoplastic lesions in the mammary gland of pregnant mice, apparently by directly targeting MaSCs, and implicates BPA as an exogenous endocrine factor that may promote pregnancy-associated mammary tumorigenesis.
Citation Format: Hakim Bouamar, Fuchuang Zhang, Xiang Gu, Qiaoxiang Dong, Lu-Zhe Sun. Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3308.
Abstract 3318: Exploring the utility of natural and synthetic resveratrol derivatives for bone regrowth following loss due to breast cancer therapies
Authors: Robert Evan , Rhodes Lyndsay V. 
Published: July 2016

Abstract
Many of the most widely used therapies for the treatment of breast cancer have been associated with enhanced rate of bone loss, including chemotherapies and hormone therapies, due to alteration of normal hormone signaling. Bone loss is due to a shift in the balance between osteoblast and osteoclast cells that are derived from a common precursor, mesenchymal stem cells (MSC), found in the bone marrow. Estrogen is an important mediator of both hormone-responsive breast cancers and normal bone development and regeneration, favoring MSC differentiation down the osteoblast lineage. Stilbenes, defense compounds produced by plants including red grapes, peanuts, and blueberries, have been popularized in recent years based on observed health benefits. Resveratrol, the most widely studied stilbene, has been credited with many health benefits including cardiovascular health, anti-cancer and antioxidant effects, and inhibition of obesity and diabetes. Many stilbenes, including resveratrol can be classified as phytoestrogens due to their ability to bind and alter the activity of the estrogen receptor. A series of 28 stilbene compounds, including resveratrol and pterostilbene, were obtained by the U.S. Department of Agriculture and screened for effects on MSC differentiation. MSC were treated with stilbene compounds (both E and Z isoforms) and cultured in either osteogenic or adipogenic differentiation media for 7-21 days. Following differentiation, cells were stained with (1) Alizarin Red S to identify calcium deposits or (2) Oil Red O to identify lipid droplets. Several compounds were found to stimulate osteogenesis while inhibiting adipogenesis and were selected for further study and development. Realtime PCR for known genes associated with osteogenesis (ALPL, RUNX2, OCN, OPN) and adipogenesis (ADIPOQ, GLUT4, LEP, PPARG) were used to confirm differentiation and gain insight into the mechanism of altered differentiation. Unlike estrogen, stilbenes do not appear to negatively impact breast and reproductive organs. Stilbenes thus represent a novel option for inducing a preferential shift of MSCs toward the osteogenic lineage while potentially avoiding the negative health effects of estrogen. Targeting the differentiation of MSC to favor bone formation represents a viable target for the development of novel therapeutics for bone loss following cancer treatment. Further, identifying compounds that stimulate osteogenesis while repressing adipogenesis could benefit other metabolic disorders like obesity associated with increased breast cancer risk.
Citation Format: Evan Robert, Lyndsay V. Rhodes. Exploring the utility of natural and synthetic resveratrol derivatives for bone regrowth following loss due to breast cancer therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3318.
Abstract 3321: PUMA expression targets αvβ3/Slug+ “stem-like” tumor cells to prevent breast cancer progression independent of subtype
Authors: Sun Qi , Lesperance Jacqueline , Desgrosellier Jay S. 
Published: July 2016

Abstract
Breast cancer cells bearing similarities to normal mammary stem cells represent some of the most aggressive tumors cells. Here, we show that αvβ3/Slug+ “stem-like” tumor cells are highly vulnerable to cell death induced by PUMA (p53-upregulated modulator of apoptosis). In human breast cancers, we were surprised to find that αvβ3/Slug+ cells represent a unique subset of tumor cells associated with progression that are present in all major histological subtypes. Analysis of “stem-like” cell lines showed that αvβ3 directs an EMT-independent role for Slug in suppressing PUMA expression and promoting tumor cell survival and stemness. In fact, αvβ3 is both necessary and sufficient for PUMA suppression and PUMA knockdown specifically rescued defective colony formation and tumor initiation caused by decreased β3 expression. Inducing PUMA expression with specific therapies selectively ablated αvβ3/Slug+ cells, preventing the formation of new colonies or tumors, with no effect on established disease. These new findings define an unexpected role for αvβ3/Slug-mediated PUMA suppression in driving stemness and suggest that inducing PUMA with specific therapies can selectively target “stem-like” breast cancer cells to prevent aggressive disease.
Citation Format: Qi Sun, Jacqueline Lesperance, Jay S. Desgrosellier. PUMA expression targets αvβ3/Slug+ “stem-like” tumor cells to prevent breast cancer progression independent of subtype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3321.
Abstract 3325: Combination of DNMT and HDAC inhibitors reprogram cancer stem cell signaling to overcome drug resistance
Authors: Pathania Rajneesh , Kolhe Ravindra B. , Ramachandran Sabarish , Mariappan Gurusamy , Thakur Priyanka , Prasad Puttur D. , Ganapathy Vadivel , Thangaraju Muthusamy 
Published: July 2016

Abstract
In recent years, impressive technical advancements have been made in the isolation and validation of the mammary stem cells (MaSCs) and cancer stem cells (CSCs). However, the signaling pathways that regulate stem cell self-renewal are largely unknown. Further, CSCs are believed to contribute to resistance to chemotherapy and radiation therapy. However, an effective therapeutic strategy to overcome this resistance is yet to be identified. We have recently discovered that the DNA methyltransferases, especially DNMT1, play critical role in MaSCs and CSCs self-renewal and targeted deletion of this gene impaired mammary tumor formation by inhibiting CSCs formation. However, the molecular mechanism(s) by which DNMTs control CSCs and the therapeutic relevance of DNMTs inhibitors in regulation of CSCs and overcome drug resistance are also largely unknown. In this study, using MMTV-Neu-Tg mouse mammary tumor model, we found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which leads to activation of un-activated Neu-Tg into transformed tumor forming phenotype. Combination of 5-Azacytidine, a DNMT inhibitor, and butyrate, a HDAC inhibitor, markedly reduces CSCs and consequently increases the overall survival of the animal. RNA-seq analysis of the CSCs treated with 5-AzaC+butyrate provides evidence that combined inhibition of DNMTs and HDACs reduces CSCs pool in the mammary gland by blocking growth-promoting signaling molecules like RAD51AP1 and SPC25. RAD51AP1 and SPC25, which are known to play a key role in DNA damage repair and kinetochore assembly, are significantly overexpressed in breast tumor tissues and associated with decreased overall patients’ survival. Further, these two genes are overexpressed in Tamoxifen and Taxol resistant human breast cancer cell lines. Functional inactivation of these genes in breast caner cells facilitates chemotherapy-induced apoptosis and reduces tumor growth. Overall, our studies provide strong evidence that breast CSCs (both basal stem cells and luminal progenitor cells) are susceptible for genetic and epigenetic modifications and associated with resistance to chemo- and radiotherapy. Thus, combination of DNMT and HDAC inhibitors can serve as an effective therapeutic strategy to block mammary tumor growth and to overcome drug resistance by inhibiting CSCs.
Citation Format: Rajneesh Pathania, Ravindra B. Kolhe, Sabarish Ramachandran, Gurusamy Mariappan, Priyanka Thakur, Puttur D. Prasad, Vadivel Ganapathy, Muthusamy Thangaraju. Combination of DNMT and HDAC inhibitors reprogram cancer stem cell signaling to overcome drug resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3325.
Abstract 3331: RP6530, a dual PI3K δ/γ inhibitor attenuates cancer stem cell proliferation in serous adenocarcinoma of ovary
Authors: S Sneha , R Nivetha , Viswanadha Srikant , Vakkalanka Swaroop , TS Ganesan 
Published: July 2016

Abstract
The overall survival of patients with advanced serous adenocarcinoma of the ovary (EOC) has not significantly improved for the past 3 decades despite advances in treatment. In part, this is due to resistance of malignant cells and it is currently hypothesized that this could be due to persistence of cancer stem cells (CSC). Elimination of these cells may improve the survival of patients. RP6530 is a novel, potent, and selective PI3K δ/γ inhibitor that demonstrated high potency against PI3Kδ (IC50 = 25 nM) and γ (IC50 = 33 nM) enzymes with selectivity over α (&gt;300-fold) and β (&gt;100-fold) isoforms. A Phase-1 dose-escalation study to evaluate the safety and efficacy of RP6530 in patients with hematological malignancies in currently underway at several sites in Europe. The objective of this study was to test the efficacy of RP6530 against the CSC of EOC. A spheroid assay enriched for CSC was employed for this study. Initially, we have analyzed 3 cell lines (PEO4, OVCAR-5 and CAOV-2) with and without addition of 5 μM RP6530. In addition, MTT assay for cell viability was performed for the molecule to evaluate for non-selective cytotoxicity. To confirm that the target was CSC, we performed analysis of Side population (SP) based on H33342 dye exclusion. In the screening assay (triplicate and repeated thrice), RP6530 significantly inhibited spheroid formation in PEO4 and OVCAR-5 (p&lt;0.05) and CAOV-2 (p&lt;0.0005). In the cell viability assay, RP6530 had no cytotoxic effect in any of the cell lines. To evaluate the effect of the compound on CSC, we performed analysis of SP cells with Hoechst 33342 at 355 nm by flow cytometry. RP6530 either caused a reduction in the fraction of SP cells (PEO4 and CAOV-2) or was neutral (OVCAR-5) indicating that the compound preferentially targets CSC in ovarian cancer cell lines. Further in vitro and in vivo experiments are ongoing to conclusively prove this effect.
Citation Format: Sneha S, Nivetha R, Srikant Viswanadha, Swaroop Vakkalanka, Ganesan TS. RP6530, a dual PI3K δ/γ inhibitor attenuates cancer stem cell proliferation in serous adenocarcinoma of ovary. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3331.
Abstract 3343: Targeting the Lin28A/B axis reverts stem cell-like phenotype and tumor-initiating properties in prostate cancer
Authors: Albino Domenico , Civenni Gianluca , Dallavalle Cecilia , Roos Martina , Jahns Hartmut , Hall Jonathan , Carbone Giuseppina M. , Catapano Carlo V. 
Published: July 2016

Abstract
Cancer stem cells (CSCs) represent the most tumorigenic, metastatic and therapy resistant cell subpopulation within human tumors. Current therapies target bulk tumor cells while spare the most aggressive CSC subpopulation. Understanding the mechanisms responsible for the acquisition and maintenance of the CSC phenotype will help to identify new strategies to target CSCs. In this study, we describe a link between deregulated expression of the ETS transcription factor ESE3/EHF and upregulation of Lin28A and Lin28B in prostate CSC-enriched subpopulations. Furthermore, using various cell line models and in vitro/in vivo experimental systems we demonstrate the efficacy of targeting the Lin28A/B axis for selective elimination of cancer cells with tumor-initiating and stem-like properties. Mechanistically, we found that ESE3/EHF represses transcription of Lin28A and Lin28B in normal prostate epithelial cells. Downregulation of ESE3/EHF in prostate tumors led to upregulation of Lin28A and Lin28B and consequent reduction of microRNAs (miRNAs) of the let-7 family, which exert tumor suppressor functions. These events promoted cell transformation and expansion of the prostate CSC subpopulation. Conversely, targeting Lin28A/Lin28B with small interfering RNAs (siRNAs) in transformed prostate epithelial cells and prostate cancer cell lines restored the levels of let-7 miRNAs, decreased expression of several CSC marker genes, and restrained tumor-sphere formation and self-renewal properties in vitro and tumor-initiating capability in vivo. Notably, systemic treatment with a siRNA targeting Lin28B reduced growth of prostate tumor xenografts in mice. This was associated with a significant contraction of the CSC subpopulation in tumor xenografts, as demonstrated by the reduced content of ex vivo tumor-sphere forming cells, reduced expression of CSC marker genes, and upregulation of let-7 miRNAs. Furthermore, tumor cells derived from siLin28B-treated xenografts exhibited reduced in vivo tumor-initiating and self-renewal capability, in line with a persistent loss of CSC properties. Collectively, these data establish the Lin28/let-7 axis as a critical element in malignant transformation and acquisition of tumor-initiating and stem-like properties and identify a valid therapeutic strategy to antagonize CSCs in human prostate cancer.
Citation Format: Domenico Albino, Gianluca Civenni, Cecilia Dallavalle, Martina Roos, Hartmut Jahns, Jonathan Hall, Giuseppina M. Carbone, Carlo V. Catapano. Targeting the Lin28A/B axis reverts stem cell-like phenotype and tumor-initiating properties in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3343.
Abstract 3355: Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating cells
Authors: Lundholm Lovisa , Hååg Petra , Eriksson Mina , Brzozowska Beata , Lewensohn Rolf , Wojcik Andrzej , Viktorsson Kristina 
Published: July 2016

Abstract
Tumors are suggested to be highly responsive to epigenetic alterations such as histone modifications and DNA methylation. We have previously reported a resistant phenotype of sphere-forming non-small cell lung cancer (NSCLC) tumor initiating cells (TICs) with an impaired activation of DNA-damage response proteins. Here we set out to analyze chromatin compactness since a heterochromatic structure has been postulated to constitute a barrier to DNA damage and repair. We show that certain NSCLC and small cell lung cancer (SCLC) TICs have elevated levels of the heterochromatin markers heterochromatin protein 1γ (HP1γ) and trimethylated lysine 9 of histone 3 (H3K9me3). Chromatin modulators were tested and histone deacetylase inhibitors (HDACi) vorinostat, panobinostat and trichostatin A reduced the cell viability of NSCLC TICs compared to bulk cells after 72 h. We could also demonstrate that TICs are more responsive to HDAC inhibitors since the euchromatin marker acetylated lysine 8 of histone H4 (H4K8ac) was increased after vorinostat and trichostatin A in NSCLC TICs but not in bulk cells. Pretreatment with HDACi inhibitors sensitized NSCLC TICs to cisplatin and ionizing irradiation. Accordingly, pretreatment with vorinostat increased the phosphorylation of the DNA-damage response proteins ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) upon irradiation in NSCLC TICs, whereas bulk cells already had a higher level with radiation only. In conclusion, we demonstrate that lung cancer TICs display a heterochromatic structure compared to bulk cells and that NSCLC TICs have an enhanced sensitization upon DNA damage inflicted by cisplatin or radiation after HDACi pretreatment.
Citation Format: Lovisa Lundholm, Petra Hååg, Mina Eriksson, Beata Brzozowska, Rolf Lewensohn, Andrzej Wojcik, Kristina Viktorsson. Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3355.