bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1968: A novel glucocorticoid receptor (GR) antagonist overcomes GR-mediated chemoresistance in triple-negative breast cancer
Authors: Jahchan Nadine , Zhou Haiying , Kong Wayne , Weeney Dan Mc , Tracy Ted , Stice James , Sutimantanapi Dena , Chen Chelsea , Huang Tom , Rew Yosup , Du Xiauhui , Zavorotinskaya Tatiana , Sun Daqing , Ye Qiuping , Jackson Erica , Fantin Valeria 
Published: August 2018

Abstract
The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily, which is activated by its endogenous steroid hormone ligand cortisol, and by synthetic glucocorticoids such as dexamethasone. Several preclinical studies have shown that GR mediates resistance to both targeted therapies and conventional chemotherapies in a variety of epithelial cancers including prostate, lung, bladder, renal, ovarian and triple-negative breast cancers (TNBC) (Gassler et al., 2005; Li et al., 2017; Zhang et al., 2007). In TNBC, both GR activation and a disrupted cortisol secretion cycle are associated with chemotherapy resistance, increased disease recurrence and poor prognosis (Pan et al., 2011; Skor et al., 2013). Therefore a molecule that inhibits GR activation could attenuate the development of therapy resistance and improve patient outcomes. We have developed novel GR inhibitors that effectively block GR transcriptional activity in cells by competing for ligand binding and by blocking GR-coactivator interactions. In vitro, treatment of TNBC cells with the GR antagonist OP-3713 blocks GR transcriptional activity and enhances the efficacy of chemotherapeutic agents. In rodents the predominant glucocorticoid is corticosterone (Siswanto et al., 2008), which is a weak agonist of human GR. Therefore, to fully activate GR in human xenograft cancer models it is necessary to provide exogenous cortisol. Using xenograft models of TNBC, we find that tumors grown in mice with physiologically relevant circulating cortisol levels to activate GR are significantly less sensitive to chemotherapy than those grown in the absence of cortisol. Furthermore, inhibition of GR by OP-3713 prevents tumor relapse following chemotherapy treatment. We have begun to elucidate the mechanisms by which GR mediates chemoresistance in TNBC, and the basis for the reversal by OP-3713. Our findings underscore the important role of GR as a mediator of resistance in TNBC and highlight the therapeutic potential of GR inhibitors in combination with clinically relevant chemotherapeutic agents.
Citation Format: Nadine Jahchan, Haiying Zhou, Wayne Kong, Dan Mc Weeney, Ted Tracy, James Stice, Dena Sutimantanapi, Chelsea Chen, Tom Huang, Yosup Rew, Xiauhui Du, Tatiana Zavorotinskaya, Daqing Sun, Qiuping Ye, Erica Jackson, Valeria Fantin. A novel glucocorticoid receptor (GR) antagonist overcomes GR-mediated chemoresistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1968.
Abstract 1992: Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity
Authors: Dravis Christopher , Chung Chi-Yeh , Wahl Geoff 
Published: August 2018

Abstract
Cell state reprogramming during tumor progression significantly contributes to the genesis of intra-tumoral heterogeneity. Discovering how cell state plasticity is specified during normal mammary development, and how this relates to breast cancer, could provide new treatment approaches. We used chromatin accessibility assays and transcriptional profiling to infer lineage potential within distinct normal mammary cell populations. We show that fetal and adult basal cells exhibit features consistent with multi-lineage differentiation potential. SOX family transcription factor DNA-binding motifs were enriched in the open chromatin of stem/progenitor cells, implicating SOX factors in mammary cell plasticity. We provide evidence that SOX10 expression correlates with multiple indicators of cell state plasticity, and that it directly contributes to tumor development in multiple animal models. Strikingly, we show that SOX10-positive tumor cells uniquely exhibit neural crest cell features, and that SOX10 binds to genes that regulate neural crest cell identity. Collectively, these data help to resolve conflicts concerning cell fate and cell potential in the mammary cell hierarchy, reveal that SOX10 is a plasticity factor driving mammary tumor progression, and demonstrate the remarkable scope of cell state reprogramming that can occur during tumorigenesis.
Citation Format: Christopher Dravis, Chi-Yeh Chung, Geoff Wahl. Epigenetic and transcriptomic profiling of mammary gland development and tumor models disclose regulators of cell state plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1992.
Abstract 1999: Study of CD44 variant 6 (CD44v6) in prostate cancer chemo-/radio resistance in vivo
Authors: Ni Jie , Cozzi Paul , Beretov Julia , Bucci Joseph , Graham Peter , Li Yong 
Published: August 2018

Abstract
Background: Chemo-/radio-resistance is an important reason for prostate cancer (CaP) progression and metastasis. CD44 is a well-documented cancer stem cell (CSC) biomarker, and one of its variants, CD44 variant 6 (CD44v6) is closely associated with aggressive behaviour and correlates with poor prognosis in a variety of human cancers. Our previous study has demonstrated increased expressions of CD44v6 in metastatic CaP cell lines and human CaP tissues, which was associated with CaP progression and chemo-/radio-resistance in vitro. However, the role of CD44v6 in CaP progression and therapeutic resistance in vivo is still uncertain.
Aim: The aim of this study was to investigate the role of CD44v6 in CaP development and chemo-/radioresistance as well as underlying pathways in vivo, and find whether it is a suitable therapeutic target for CaP therapy.
Methods: CD44v6 gene was knocked down (KD) in PC-3M CaP cell line using short hairpin RNA (shRNA). Subcutaneous (s.c.) and orthotopic CaP animal models were established using PC-3M-CD44v6-KD and PC-3M-CD44v6-scramble (scr) control cells, to assess the effect of CD44v6 on CaP tumourigenesis, chemotherapy (docetaxel) response and radiation response. Signal transduction proteins in PI3K/Akt/mTOR pathway (Akt, p-Akt, mTOR and p-mTOR) as well as proliferation and apoptosis makers were assessed by immunohistochemistry in xenografts from both animal models.
Results: Both s.c. and orthotopic xenografts from PC-3M-CD44v6-KD cells displayed supressed tumour growth and increased responsiveness to docetaxel (40mg/kg) and radiation (2Gy/day for 4 consecutive days) compared to control xenografts from PC-3M-CD44v6-scr cells in NOD/SCID male mice. Down-regulation of the PI3K/Akt/mTOR pathway proteins (p-Akt and p-mTOR), proliferation marker (Ki-67) and angiogenesis marker (CD31), as well as up-regulation of apoptotic responses (cleaved Caspase-3) to chemotherapy, DNA damage responses (γ-H2AX) to radiation were found in PC-3M-CD44v6-KD s.c. xenografts, respectively.
Conclusions: CD44v6 is actively involved in CaP tumorigenesis and treatment responses to chemo-/radio-therapy via PI3K/Akt/mTOR signalling pathway in in vivo mouse models and holds promise as a therapeutic target for the treatment of CaP.
Key words: CD44v6, prostate cancer, chemo-/radio-resistance, animal model, metastasis
Citation Format: Jie Ni, Paul Cozzi, Julia Beretov, Joseph Bucci, Peter Graham, Yong Li. Study of CD44 variant 6 (CD44v6) in prostate cancer chemo-/radio resistance in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1999.
Abstract 2002: Ganoderma lucidum extract (GLE) reduces stem cell markers in triple-negative breast cancer models via STAT3 regulation
Authors: Rios Tiffany J. , Marti Alicia , Ortiz Gabriela , Martínez-Montemayor Michelle M. 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is a subtype of cancer described by the lack of estrogen receptor, progestogen receptor, and HER2 receptor. It accounts for approximately 15-20% of all breast cancer (BC) cases worldwide. TNBC aggressiveness might be explained by the presence of BC stem cells (BCSCs), which are a subpopulation of cancer cells involved in tumor initiation, metastasis, and therapy resistance. Interestingly, the signal transducer and activator of transcription 3 (STAT3) participates in the development and progression of BCSCs, but its role in TNBC progression remains unclear. Moreover, BCSCs can be identified by the CD44+/CD24- and ALDH+ phenotype, which correlates with a worse prognosis in TNBC patients. Furthermore, CSCs can be characterized based on the expression of transcription factors involved in stemness (Nanog, Sox2, and Oct4A), where activation of STAT3 leads to enhanced Nanog, Oct4 and Sox2 expression. Importantly, a major challenge arises to develop nontoxic targeted therapies to improve the outcome of TNBC patients. In this regard, our laboratory investigates the role of Ganoderma lucidum extract (GLE), a medicinal mushroom commonly used in complementary and alternative medicine. We hypothesize that GLE will decrease stem cell properties via STAT3 regulation in TNBC cells. Our in vitro results demonstrate that GLE significantly downregulates STAT3 and JAK2 in SUM-149 and MDA-MB-231, TNBC cell lines. In addition, GLE significantly decreases the secretion of IL-6 at 24hr in MDAMB231 cells. Further flow cytometry results show that GLE significantly decreases the CD44+/CD24- population at 24hr and 72hr in MDA-MB-231 cells. In this regard, GLE significantly decreases the expression of ALDH at 24hr and 72hr in MDAMB231 cells. Moreover, GLE decreases the expression of Nanog at 24hr, and all three transcription factors at 72hr. Additionally, our in vivo studies demonstrate that GLE significantly decreases tumor volume of mice injected with CD44+/CD24- sorted cells of the MDA-MB-231 cell line. Finally, tumor weight of GLE treated mice was marginally significantly lower (p=0.053) compared to vehicle. We can conclude that GLE decreases stemness of TNBC via STAT3 regulation.
Citation Format: Tiffany J. Rios, Alicia Marti, Gabriela Ortiz, Michelle M. Martínez-Montemayor. Ganoderma lucidum extract (GLE) reduces stem cell markers in triple-negative breast cancer models via STAT3 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2002.
Abstract 2009: Breast cancer stem cells are associated with HER2-mediated radioresistance and the molecular subtype conversion of HER2-negative breast cancer
Authors: Kim Jae-Sung 
Published: August 2018

Abstract
Although it has been proposed that the benefits of HER2-targeted therapy in HER2-negative breast cancer are associated with molecular subtype conversion, the underlying mechanism and the clinical biomarkers are unclear. Herein, we showed that breast cancer stem cells (BCSCs) mediate HER2 subtype conversion and radioresistance in HER2-negative breast cancer cells and evaluated serum HER2 as a clinical biomarker for HER2 subtype conversion. We found that the CD44+/CD24-/low BCSCs from HER2-negative breast cancer cells overexpressed HER2/EGFR and showed the radioresistant phenotype. In addition, we showed that trastuzumab treatment sensitized the radioresistant phenotype of the CD44+/CD24-/low cells with decreased levels of HER2/EGFR, which suggested that HER2-targeted therapy in HER2-negative breast cancer may be effective by targeting BCSCs that overexpress HER2/EGFR. Importantly, our clinical data showed that serum HER2 could be a clinical biomarker for the evaluation of HER2 subtype conversion in recurrent HER2-negative breast cancer patients. Therefore, our data provide in vitro and in vivo evidence for the molecular subtype conversion of HER2-negative breast cancer.
Citation Format: Jae-Sung Kim. Breast cancer stem cells are associated with HER2-mediated radioresistance and the molecular subtype conversion of HER2-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2009.
Abstract 2021: The CXCL12/CXCR4 axis drives epithelial-mesenchymal transition in renal cell carcinoma
Authors: Zhilin-Roth Alisa , Macoska Jill A. 
Published: August 2018

Abstract
Introduction. Renal cell carcinoma (RCC) is the one of the most common cancers diagnosed in adult men with more than 40000 new cases annually. Recurrence or metastasis of the disease occurs in more than 30% of patients and death from disease occurs in most of these patients due to limited therapeutic options. Clearly, a better understanding of factors contributing to RCC metastasis might improve therapeutic development and patient outcomes. One of the steps required for tumor cell progression from localized disease to metastatic disease is the acquisition of invasive abilities through epithelial to mesenchymal transition (EMT). EMT promotes loss of epithelial markers by downregulation of E-cadherin, gain of mesenchymal markers like Vimentin, and N-cadherin, and cytoskeletal rearrangement that enables cells to leave the primary site and intravasate into the blood or lymphatic systems and thereby colonize distant sites. Metastasis and colonization are highly directed mechanisms in which cancer cells migrate toward specific preferred organs that express specific protein receptors. One of these receptors is CXCR4, which is upregulated in advanced cancer including RCC and is correlated with poor survival. In this study we explored the hypothesis that CXCR4/CXCL12 signaling promotes migratory ability by inducing EMT in vitro in the RCC cell lines Caki-2 and 786-0.
Methods. To pursue these studies we utilized in vitro mammalian cell culture, cell proliferation (WST) assays, cell migration (scratch) assays, and protein analysis methods including immunoblot and immunofluorescence.
Results. These studies showed that RCC cell lines express CXCR4 that is activated by CXCL12 to induce cellular proliferation and promote a wound healing migratory response dependent on EMT cytoskeletal rearrangement by Rho GTPases. Moreover, CXCR4/CXCL12 induces down-regulation of E-cadherin, up-regulation of vimentin, N-cadherin and the upregulation of EMT transcription factors SLUG/SNAIL, consistent with EMT signaling activation. Lastly, CXCR4/CXCL12 activation promotes phosphorylation of AKT and ERK, suggesting that these signaling pathways are coupled to CXCR4/CXCL12-mediated RCC progression.
Conclusions. Our findings suggest that CXCR4/CXCL12 activation in RCC has a pivotal role in EMT induction by the acquisition of a migratory and invasive phenotype. Understanding the underlying signaling pathways employed by the CXCL12/CXCR4 axis may shed new light on the migration/ invasion mechanisms that allow RCC cells to spread to distant organs and assist with the design and testing of new therapeutic strategies to treat advanced metastatic RCC.
Citation Format: Alisa Zhilin-Roth, Jill A. Macoska. The CXCL12/CXCR4 axis drives epithelial-mesenchymal transition in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2021.
Abstract 2068: Single-cell RNA-seq profiling of the transcriptional response to Rb loss in the retinoblastoma cell of origin
Authors: Lee Sunhye , Singh Hardeep P. , Triska Martin , Stachelek Kevin T. , Bay Maxwell M. , Grubbs Brendan H. , Thronton Matthew E. , Hu Haoze , Segil Neil I. , Bonaguidi Michael A. , Cobrinik David 
Published: August 2018

Abstract
Retinoblastoma is a rare childhood tumor initiated by biallelic inactivation of the RB1 gene and loss of functional retinoblastoma (Rb) protein. The tumors are thought to originate in cone photoreceptor precursors since Rb knockdown induces cone precursor proliferation and elicits cone-precursor-derived retinoblastoma-like tumors in orthotopic grafts. The identification of the retinoblastoma cell of origin and the authentic initiating mutation presents an opportunity to define the detailed molecular mechanisms controlling malignant transformation of a human cancer. In this project, we seek to define the transcriptional and epigenetic cell state transitions that follow Rb depletion as post-mitotic human cone precursors are induced to re-enter the cell cycle. Prospectively isolated cone precursors were transduced with lentivirus carrying either of three RB1 shRNAs or a SCR control shRNA and then re-isolated by FACS. Single cell RNA-sequencing (scRNA-seq) was performed at multiple time points over 15 days by generating full-length cDNAs corresponding to polyadenylated RNAs followed by sequencing. Among the 572 individual cells that passed quality control, an average of 6.6 million mapped reads and ~21,000 genes (~93,000 transcript isoforms) were detected per transcriptome. In addition, 300 cells per shRNA group were evaluated for genome-wide open chromatin using uATAC-seq at day 0 and 15. Cell transcriptomes were pseudotemporally ordered using “Waterfall” in order to define cellular trajectories and corresponding transcriptomic responses to Rb loss. Using transcriptomic, epigenetic, and network analyses, we define cell state transitions and identify potential mediators of such transitions, that are associated with the initiation of retinoblastoma development.
Citation Format: Sunhye Lee, Hardeep P. Singh, Martin Triska, Kevin T. Stachelek, Maxwell M. Bay, Brendan H. Grubbs, Matthew E. Thronton, Haoze Hu, Neil I. Segil, Michael A. Bonaguidi, David Cobrinik. Single-cell RNA-seq profiling of the transcriptional response to Rb loss in the retinoblastoma cell of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2068.
Abstract 2083: Innate immunity polymorphisms and risk of pediatric cancer
Authors: Mercado Gabriela E. , Rosales-Bravo Gabriela A. , Velazquez-Fernandez David , Zapata-Tarres Marta , Juarez-Villegas Luis E. 
Published: August 2018

Abstract
In Mexico, cancer represents the second leading cause of death in the pediatric population. The identification of susceptibility genes associated with cancer has been one of the main challenges of human genomics. Several studies have proposed that genetic variation in immune-related genes could be a determinant of susceptibility in different types of cancer. In the present study we evaluated the possible association between 10 polymorphisms in genes that participate in innate immunity and the risk of pediatric cancer. We analyzed genotyping data from 101 patients from Hospital Infantil de México “Federico Gómez” (HIM) with confirmed diagnosis of pediatric cancer. The genotypes were compared with 274 healthy adults without a medical history of pediatric cancer. For each polymorphism we calculated allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE). The association between cancer and pediatric cancer was analyzed using Pearson chi-square and odds ratio (OR); survival analyses were performed by the log rank test and Kaplan-Meier curves. Our results show that risk of pediatric cancer in our sample is significantly associated with the genetic variants IL8-251 (p= 0.04327, OR= 0.701, IC 95% = 0.496-0.990), IL6-174 (p= 0.0037, OR= 2.413, IC 95% = 1.310-4.445), and IL10-592 (p= 0.0062, OR= 0.670, IC 95% = 0.502-0.894). However, we did not find any significant association between selected polymorphisms and overall or disease-free survival.
Citation Format: Gabriela E. Mercado, Gabriela A. Rosales-Bravo, David Velazquez-Fernandez, Marta Zapata-Tarres, Luis E. Juarez-Villegas. Innate immunity polymorphisms and risk of pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2083.
Abstract 2109: Prognostic and functional significance of interleukin 22 in colorectal cancer
Authors: Cremonesi Eleonora , Tosti Nadia , Amicarella Francesca , Weixler Benjamin , Däster Silvio , Governa Valeria , Spagnoli Giulio C. , Terracciano Luigi , Tornillo Luigi , Eppenberger-Castori Serenella , Iezzi Giandomenica , Droeser Raoul 
Published: August 2018

Abstract
T cell infiltration has been recognized to significantly impact clinical outcome in human colorectal cancer (CRC). Interleukin 22 (IL-22), a cytokine secreted by IL-17-producing CD4+ T cells (Th17) is known to play a crucial role in inflammatory bowel disease and has been shown to have protumorigenic activity in mouse tumor models. However, its role in human CRC is still unclear. In a previous study we could demonstrate the dual role of Th17 in CRC. As consequence we evaluated the prognostic and functional impact of IL-22 producing cells in human CRC in this follow-up study. Upon staining of a tissue microarray (TMA), including 423 CRC cases, IL-22 positive cells were detected both within tumor cells and tumor infiltrating immune cells. Whereas, IL-22 expression by tumor cells did not impact on prognosis, densities of IL-22 positive immune cells were found to be significantly associated with early T stage and MMR-deficient microsatellite stability. Importantly, IL-22 expression by CRC infiltrating immune cells was predictive of improved overall survival independent of known prognostic factors such as T stage, N stage, tumor grade, vascular invasion, tumor border configuration and MMR status. Phenotypic characterization of IL-22 positive cells performed by flow cytometry revealed that they consist mainly of Th17 cells, also producing IL-17. In vitro experiments showed no direct effect of IL-22 on CRC cell proliferation. On-going studies are validating the prognostic effect on a TMA cohort with corresponding transcriptomic data and evaluating potential effects mediated by IL-22 on other cell types of CRC microenvironment.
Citation Format: Eleonora Cremonesi, Nadia Tosti, Francesca Amicarella, Benjamin Weixler, Silvio Däster, Valeria Governa, Giulio C. Spagnoli, Luigi Terracciano, Luigi Tornillo, Serenella Eppenberger-Castori, Giandomenica Iezzi, Raoul Droeser. Prognostic and functional significance of interleukin 22 in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2109.