bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-142: Functional role of DNA methyltransferase1 (DNMT1) in regulation of mammary stem/progenitor and cancer stem cells
Authors: Pathania Rajneesh , Ramachandran Sabarish , Prasad Puttur , Ganapathy Vadivel , Thangaraju Muthusamy 
Published: August 2015

Abstract
Tumor propagation is the hallmark feature of the cancer stem/tumor propagating cells. Several genetic and epigenetic components are involved in regulation of this process; however, DNA methylation provides a potential epigenetic mechanism for the cellular memory, which needed to preserve the tumorigenic potential through repeated cell divisions. Further, DNA methylation plays a critical role in stem/progenitor cell maintenance wherein the DNMT proteins get enriched in undifferentiated cells and thereby it retains the regenerative capacity while suppressing differentiation. However, the precise role of DNMTs in maintaining stem/progenitor and tumorigenic phenotype in constantly replenished organ, like mammary glands and mammary tumor is not yet known. Here we show that Dnmt1 is required for mammary gland outgrowth and terminal end bud development and that mammary-gland specific Dnmt1 deletion in mice leads to significant reduction in mammary stem/progenitor cell formation. Interestingly, Dnmt1 deletion almost completely abolishes Neu-Tg- and C3(1)-SV40-Tg- driven mammary tumor formation and metastasis. This phenomenon is associated with significant reduction in cancer stem cell (CSC) formation. Similar observations were also recapitulated using pharmacological inhibitors of Dnmts in Neu-Tg mice. To unravel the cause of tumorigenicity of tumor propagating cells, we used genome-wide methylation and RNA sequence approach and find that DNA methylation plays a vital role in regulation of abnormal self-renewal by hypermethylating genes that are involved in development and cell commitment pathways; thereby leading to immortality and autonomous growth to the tumor propagating cells. Overall, our studies provide the first in vivo evidence that DNMT1 is indispensable for mammary stem, progenitor and cancer stem cell formation and that functional inactivation of this gene drastically reduces mammary tumor formation even in the aggressive triple-negative breast cancer subtype. Furthermore, we identified ISL1 as a functional target of DNMT1 in tumor progenitor cells, and stable expression of ISL1 induces apoptosis in cancer stem cells. Thus, DNMT1 specific inhibitors could have a great impact on eradication of cancer stem cells and associated disease recurrence, and ISL1 hypermethylation status could be used as a prognostic marker for early breast cancer diagnosis.
Citation Format: Rajneesh Pathania, Sabarish Ramachandran, Puttur Prasad, Vadivel Ganapathy, Muthusamy Thangaraju. Functional role of DNA methyltransferase1 (DNMT1) in regulation of mammary stem/progenitor and cancer stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-142. doi:10.1158/1538-7445.AM2015-LB-142
Abstract LB-146: TGF-β-induced tumor heterogeneity and drug resistance of cancer stem cells
Authors: Oshimori Naoki , Oristian Daniel , Fuchs Elaine 
Published: August 2015

Abstract
Among the most common and life-threatening cancers world-wide, squamous cell carcinoma (SCC) exhibit high rates of tumor recurrence following anti-cancer therapy. Subsets of cancer stem cells (CSCs) often escape anti-cancer therapeutics and promote recurrence. However, its sources and mechanisms that generate tumor heterogeneity and therapy-resistant cell population are largely unknown. Tumor microenvironment may drive intratumor heterogeneity by transmitting signaling factors, oxygen and metabolites to tumor cells depending on their proximity to the local sources. While the hypothesis is attractive, experimental evidence is lacking, and non-genetic mechanisms that drive functional heterogeneity remain largely unknown. As a potential non-genetic factor, we focused on TGF-β because of its multiple roles in tumor progression.
Here we devise a functional reporter system to monitor, track and modify TGF-β signaling in mouse skin SCC in vivo. Using this approach, we found that perivascular TGF-β in the tumor microenvironment generates heterogeneity in TGF-β signaling in neighboring CSCs. This heterogeneity is functionally important: small subsets of TGF-β-responding CSCs proliferate more slowly than their non-responding counterparts. They also exhibit invasive morphology and a malignant differentiation program compared to their non-responding neighbors. By lineage tracing, we show that although TGF-β-responding CSCs clonally expand more slowly they gain a growth advantage in a remarkable ability to escape cisplatin-induced apoptosis. We show that indeed it is their progenies that make a substantial contribution in tumor recurrence. Surprisingly, the slower proliferating state of this subset of CSCs within the cancer correlated with but did not confer the survival advantage to anti-cancer drugs. Using transcriptomic, biochemical and genetic analyses, we unravel a novel mechanism by which heterogeneity in the tumor microenvironment allows a subset of CSCs to respond to TGF-β, and evade anti-cancer drugs.
Our findings also show that TGF-β established ability to suppress proliferation and promote invasion and metastasis do not happen sequentially, but rather simultaneously. This new work build upon the roles of this factor in tumor progression, and sets an important paradigm for a non-genetic factor that produces tumor heterogeneity.
Citation Format: Naoki Oshimori, Daniel Oristian, Elaine Fuchs. TGF-β-induced tumor heterogeneity and drug resistance of cancer stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-146. doi:10.1158/1538-7445.AM2015-LB-146
Abstract LB-154: Genome-wide analysis identified differentially methylated regions in head and neck squamous cell carcinoma anatomic subsites
Authors: Rivera Bianca L. , Folawiyo Oluwasina , Turaga Nitesh , Pirini Francesca , Lopez Ricardo , Vazquez Roger , Guerrero Rafael , Baez Adriana 
Published: August 2015

Abstract
Introduction
Several groups have identified hundreds of genes differentially methylated in head and neck squamous cell carcinoma (HNSCC) using genome-wide technologies. However, there is a paucity of studies examining differential methylation in HNSCC anatomic subsites.
Objective
Our principal objective is to determine DNA methylation differences between Head and Neck Squamous Cell Carcinoma (HNSCC) anatomic subsite: larynx, oral cavity and pharynx.
Methods
DNA was extracted from 24 HNSCC samples and 10 normal oral epithelium tissue samples of Puerto Rican Hispanic patients. To unveil the methylome of HNSCC anatomic subsites genomic DNA was enriched with Methylated DNA immunoprecipitation prior to labeling and hybridization to genome-wide oligonucleotide tilting arrays (3 × 720K Human CpG Island-Plus-Promoter Array, Roche/NimbleGen). Differentially methylated regions were identified with CHARM using the bumphunter algorithm. Downstream analyses were performed to identify differences in the methylation landscape of the three anatomic subsites: larynx, oral cavity and pharynx.
Results
When datasets were analyzed by anatomic site using DAVID v6.7 we identified 2565 differentially methylated genes common to the three subsites. We also identified 738 differentially methylated CpG loci in laryngeal cancer, 889 differentially methylated CpG loci in oral cavity and 363 differentially methylated CpG loci in pharyngeal cancer. We identified 11 key genes which were uniquely methylated in the larynx (CDH1, PAX1, BID, SMAD4, FGF19, BMP2, ITGA2, RXRA, IGFBP1, CDKN2D and RBL2). BCL2, AKT2, TRAF3, STAT5B, PTCH1, WNT9B, AXIN2, DVBL2, and APC were differentially methylated in oral cavity. In the pharynx, a comparatively lower number of differentially methylated genes were detected including B-catenin, RAF, BRAF, ATR, CTNNA1, FOXO1 and MED15.
Conclusion
We found evidence that HNSCC subsites (larynx, oral cavity and pharynx) manifest different methylation patterns that may be consistent with the clinical expression of the disease. A panel of differentially methylated genes identified will be further tested in a large cohort of HNSCC samples to determine their utility as prognostic biomarkers of HNSCC according to subsite.
Citation Format: Bianca L. Rivera, Oluwasina Folawiyo, Nitesh Turaga, Francesca Pirini, Ricardo Lopez, Roger Vazquez, Rafael Guerrero, Adriana Baez. Genome-wide analysis identified differentially methylated regions in head and neck squamous cell carcinoma anatomic subsites. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-154. doi:10.1158/1538-7445.AM2015-LB-154
Abstract LB-165: Antiproliferative effects of AZD6738 and the inhibition of DDR activity
Authors: Kim Hee Jun , Min Ahrum , Im Seock-Ah , Jang Hyemin , Lee Miso , Kim Seongyeong , Kim Jungen , Lee Kyung-Hun , Han Sae-Won , Kim Tae-Yong , Oh Do-Youn , Kim Tae-You , Bang Yung-Jue 
Published: August 2015

Abstract
Background
Anti-tumor effect of DNA damaging agents was reduced by the activation of DNA damage repair (DDR), which was led to resistance. Therefore, the inhibition of DNA repair could lead to induce the accumulation of errors which is becoming an attractive strategy. The ataxia telangiectasia and Rad3-related (ATR) proteins play a role of sensor for DNA damage, which induces homologous recombination-dependent repair. ATR is a master regulator of DDR, signaling to control DNA replication, DNA repair, and apoptosis. Therefore, the ATR pathway might be useful target for new drug development and it is important that the effects of many current cancer treatments are modulated by DDR.
Materials and Methods
The growth inhibitory effects of ATR inhibitor, AZD6738 were studied on human breast cancer cell lines using MTT assay. Cell cycle analysis and western blotting were also performed to determine molecular changes. Immunofluorescence assay and comet assay were conducted to understand the action mechanisms of AZD6738.
Results
This research identified the anti-proliferative effects and the inhibition of DDR activity by AZD6738 on human breast cancer cell lines. AZD6738 induces cell cycle arrest and apoptosis, which impaired DDR function and promoted cell death by damage accumulation. Results of MTT showed that the heterogeneous response and two cell lines were chosen for the focus on the HER2-positive breast cell lines: SKBR-3 and BT-474. In sensitive cell line, SKBR-3 cell, the expression of phosphorylated CHK1 was reduced with the other repair markers; RAD51, MRE11 and ERCC1 as opposed to less sensitive breast cancer cell BT-474. The decreased functional CHK1 leads to the accumulation of DNA damage due to homologous recombination inactivation. And it was also identified that ATR inhibitor played a role of sensitizer to increase the efficacy of cytotoxic chemotherapeutic agents, cisplatin and paclitaxel in breast cancer cell lines.
Conclusion
Understanding the antitumor efficacy and the mechanisms of ATR inhibitor in the breast cancer cell lines open up the possibility of future clinical trial targeting DNA damage repair in breast cancer
Keywords: DNA damage response, ATR inhibitor, Breast cancer, Homologous recombination
Citation Format: Hee Jun Kim, Ahrum Min, Seock-Ah Im, Hyemin Jang, Miso Lee, Seongyeong Kim, Jungen Kim, Kyung-Hun Lee, Sae-Won Han, Tae-Yong Kim, Do-Youn Oh, Tae-You Kim, Yung-Jue Bang. Antiproliferative effects of AZD6738 and the inhibition of DDR activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-165. doi:10.1158/1538-7445.AM2015-LB-165
Abstract LB-198: Molecular drivers of metabolic reprogramming during EMT
Authors: Teo Zi Qiang , Sng Ming Keat , CHAN Jeremy , Tan Nguan Soon 
Published: August 2015

Abstract
The reprogrammed cancer metabolism is an emerging cancer hallmark pervasive in many cancers and is fundamental to neoplastic progression. Many key cancer-promoting pathways are known to converge on the regulation of cellular metabolism. Besides providing basic sustenance to fuel cancer cells limitless replicative potential, emerging data reveals critical roles for the reprogammed metabolism during maglignant progression. Metastasis is often regarded as the end-stage of malignancy and majority of cancer mortality is attributed to the metastatic dissemination of the malignant cancer cells. The initiation of metastasis has been pinpointed as pivotal event, without which, the malignant cancer cells loses their motility and invasive capabilities for distal dissemination. This initiation event highly resembles epithelial-mesenchymal transition (EMT) process that occurs during embryogenesis and wound healing. Microenvironmental signals such as hypoxia and the inflammatory milleu that initiate EMT, interestingly, are also shown to be critical in rewiring cancer metabolism. Thus, it is conceivable that the manipulation of cancer metabolism can impact EMT. Furthermore, whether such metabolic reprogramming is a functional pre-requisite for the initiation of EMT remains unclear.
Using three distinct in vitro EMT models, we show that EMT is an energy-demanding process. Comparative microarray analysis of the EMT models reveals that genes involved in fatty acid, glucose and ROS metabolism are altered. We went further to show that cancer cells undergoing EMT, derives much of the ATP/energy from glucose and lipid metabolism. Importantly, we identified several key molecular drivers that coordinate EMT and cellular bioenergetics, which is validated by our in vivo EMT model.
Citation Format: Zi Qiang Teo, Ming Keat Sng, Jeremy CHAN, Nguan Soon Tan. Molecular drivers of metabolic reprogramming during EMT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2015-LB-198
Abstract LB-203: Obesity promotes resistance to anti-VEGF therapy in breast cancer via pro-inflammatory and angiogenic pathways
Authors: Incio Joao , McManus Daniel , Suboj Priya , Rahbari Nuh , Chin Shan M. , Babycutty Suboj , Vardan-Kaur Trupti , Huang Yuhui , Jung Keehoon , Duda Dan , Soares Raquel , Fukumura Dai , Jain Rakesh K. 
Published: August 2015

Abstract
Background: Most breast cancer (BC) patients are overweight or obese at the time of diagnosis. Obesity is associated with increased risk, recurrence, and worse prognosis of BC. It has been shown that obesity associates with worse outcome in metastatic kidney or colon cancer treated with bevacizumab. If and how excess body weight contributes to the failure of anti-VEGF therapy in BC is unknown.
Results: Here we found that diet-induced obesity promoted resistance to anti-VEGF therapy in two syngeneic mouse breast cancer models. The effects of anti-VEGF therapy on tumor growth and metastasis, VEGF downstream signaling pathways and vessel density were significantly attenuated in obese mice. Under obesity condition, intra-tumor adipocytes increased. These adipocyte-rich regions in breast cancers were hypoxic and overexpress IL-6 or FGF-2 by adipocytes, fibroblasts, and myeloid cells. In IL-6 overexpressing obese breast cancer model (E0771), neutralization of IL-6, either genetically or pharmacologically, abrogated the obesity-induced resistance to anti-VEGF therapy seen in both primary and metastasis sites. This occurred due to a reversion of the obesity-augmented STAT3 signaling and cell proliferation, of hypoxia via vessel normalization, and of immunosuppression. In another breast cancer model (MCaIV), which overexpress FGF-2 under obesity, anti-FGF receptor antibody restored tumor sensitivity to anti-VEGF treatment in obesity.
Conclusion: Our findings indicate that obesity promotes resistance to anti-VEGF therapy in breast cancer via the production of pro-inflammatory and angiogenic factors that circumvent the loss of VEGF signaling.
Citation Format: Joao Incio, Daniel McManus, Priya Suboj, Nuh Rahbari, Shan M. Chin, Suboj Babycutty, Trupti Vardan-Kaur, Yuhui Huang, Keehoon Jung, Dan Duda, Raquel Soares, Dai Fukumura, Rakesh K. Jain. Obesity promotes resistance to anti-VEGF therapy in breast cancer via pro-inflammatory and angiogenic pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-203. doi:10.1158/1538-7445.AM2015-LB-203
Abstract LB-242: PTEN regulates the CD20 antigen expression and affects rituximab-based therapy of lymphoma malignancies
Authors: Pyrzynska Beata , Bojarczuk Kamil , Siernicka Marta , Dwojak Michal , Bobrowicz Malgorzata , Miazek Nina , Zapala Piotr , Zagozdzon Agnieszka , Golab Jakub , Winiarska Magdalena 
Published: August 2015

Abstract
The therapeutic strategies currently used in B cell malignancies include the treatment with monoclonal antibodies (rituximab and ofatumumab) directed against CD20 antigen. These antibodies specifically eliminate B cells by triggering indirect effector mechanisms of the immune system, like complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), or immunophagocytosis. In many patients, the reduced level of CD20 antigen on the surface of tumor B cells leads to the resistance to anti-CD20 therapy. The aim of this study was to explore the molecular mechanisms governing the regulation of CD20 expression in lymphoma cells as a potential explanation of the resistance to rituximab/ofatumumab therapy.
We previously observed that CD20 mRNA expression is significantly affected by the SRC family inhibitors. Here, we report that also PTEN tumor suppressor is a negative regulator of CD20 expression. To uncover the transcriptional mechanisms governing the CD20 expression we employed the construct encoding the promoter region of CD20 cloned upstream of the firefly luciferase gene. Overexpression of wild-type PTEN (but not the phosphatase-deficient mutant) strongly affected the promoter activity and the expression of CD20, leading to decreased binding of rituximab and ofatumumab and increased resistance of tumor cells to complement-dependent cytotoxicity. Using the truncated versions of the CD20 promoter we identified a particular region (-313/-198) as the major region sensitive to PTEN overexpression. We found that the negative regulation of CD20 promoter activity by PTEN was mediated by inhibition of AKT signaling. We observed that the overexpression of constitutively active AKT1 (CA-AKT1) overcame the negative effect of PTEN and sensitized cells to rituximab/ofatumumab treatment. The results of our studies indicate that PTEN status in tumor cells should therefore be considered when analyzing the mechanisms of resistance of B cell malignancies to anti-CD20 therapies.
Citation Format: Beata Pyrzynska, Kamil Bojarczuk, Marta Siernicka, Michal Dwojak, Malgorzata Bobrowicz, Nina Miazek, Piotr Zapala, Agnieszka Zagozdzon, Jakub Golab, Magdalena Winiarska. PTEN regulates the CD20 antigen expression and affects rituximab-based therapy of lymphoma malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-242. doi:10.1158/1538-7445.AM2015-LB-242
Abstract LB-244: Amino acid deprivation selectively targets multidrug-resistant breast cancer cells
Authors: Del Vecchio Catherine A. , Feng Yuxiong , Sokol Ethan S. , Tillman Erik J. , Sanduja Sandhya , Reinhardt Ferenc , Gupta Piyush B. 
Published: August 2015

Abstract
Tumor recurrence and metastasis underlie the majority of cancer-related deaths. Cancer cells that recur or metastasize are often both de-differentiated and multidrug resistant, but the mechanistic basis for this has been poorly understood. We have recently shown that de-differentiation promotes multidrug resistance by activating Nrf2, which stimulates transcription of drug efflux pumps and enzymes that scavenge reactive oxygen species (ROS). De-differentiation activates Nrf2 by a non-canonical mechanism involving its phosphorylation by the ER membrane kinase PERK. PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy, and inhibiting this signaling axis re-sensitizes de-differentiated cancer cells to treatment. To further explore this pathway we profiled the effects of PERK inhibition on global gene expression in both differentiated and de-differentiated cells upon treatment with chemotherapy. This analysis showed that PERK inhibition results in an amino acid deprivation phenotype, and suggested that de-differentiated cells may be sensitive to perturbations in amino acid availability. Consistent with this, we found that the aminopeptidase inhibitor Tosedostat was selectively toxic to de-differentiated breast cancer cells when given in combination with chemotherapy. Our findings identify a novel vulnerability of therapy-resistant breast cancer cells, and suggest that targeting amino acid availability in combination with chemotherapy could be an effective treatment for aggressive breast cancers that are multidrug resistant.
Citation Format: Catherine A. Del Vecchio, Yuxiong Feng, Ethan S. Sokol, Erik J. Tillman, Sandhya Sanduja, Ferenc Reinhardt, Piyush B. Gupta. Amino acid deprivation selectively targets multidrug-resistant breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-244. doi:10.1158/1538-7445.AM2015-LB-244
Abstract LB-250: Induction of c-Cbl is a novel mechanism for the anti-cancer effect of HDAC inhibitor in lung cancer
Authors: Ching-Chow Chen , Wei Tzu-Tang , Lin Yu-Chin , Lin Pei-Hua , Shih Jin-Yuan , Chou Chia-Wei 
Published: August 2015

Abstract
Here we found loss of c-Cbl, an E3 ligase, expression in Non-small cell lung cancer (NSCLC) compared with its adjacent normal tissue in patient specimens. HDAC inhibition by WJ or knockdown of HDAC 1, HDAC2, HDAC3 or HDAC6 all induced c-Cbl. Ectopic expression of c-Cbl induced decreased EGFR, inhibited growth in NSCLC cells. Knockdown of EGFR inhibited NSCLC growth. Mutation of EGFR at Y1045 decreased WJ-induced growth inhibition as well as in vivo anti-cancer effect and EGFR degradation mediated by WJ. Time-lapse confocal analysis showed co-localization of c-Cbl and EGFR after WJ treatment. Furthermore, WJ inhibited lung tumor growth through c-Cbl induction in orthotopic and tail vein injected models. C-Cbl up-regulation induced by HDACi is a potential strategy for NSCLC treatment.
Citation Format: Chen Ching-Chow, Tzu-Tang Wei, Yu-Chin Lin, Pei-Hua Lin, Jin-Yuan Shih, Chia-Wei Chou. Induction of c-Cbl is a novel mechanism for the anti-cancer effect of HDAC inhibitor in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-250. doi:10.1158/1538-7445.AM2015-LB-250