bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3709: miR-21-3p: A potential oncomir in breast cancer
Authors: Amirfallah Arsalan , Arason Adalgeir , Agnarsson Bjarni A. , Johannsson Oskar Th , Hilmarsdottir Bylgja , Barkardottir Rosa Bjork , Reynisdottir Inga 
Published: September 2020

Abstract
MIR21 is a well known oncomir in many cancer types including breast cancer. Most studies that have described the oncogenic properties of MIR21 have focused on the leading strand miR-21-5p. Fewer studies have focused on the passenger strand miR-21-3p, but in a few types of cancer it has been shown to have oncogenic properties. A handful of studies suggest that miR-21-3p could be a biomarker in breast cancer. MIR21 is located at 17q23.1, a region which is often amplified in breast tumors. It overlaps the 3´ end of VMP1 but it has its own distinct promoter. The aim of this study was to analyze whether miR-21-3p associated with prognostic factors in breast cancer.
The levels of miR-21-5p and miR-21-3p were measured by qPCR in 144 breast tumors from a cohort of breast cancer patients (cohort 1). The association of expression levels with clinical and pathological factors was analyzed by Student´s t-test and Anova, and with survival by Kaplan-Meier, the log-rank test, and the Cox proportional hazards test. To confirm the results, available data were used from breast cancer cohorts from The Cancer Genome Atlas (TCGA) (n=256) and METABRIC (n=1286).
The mean expression levels of miR-21-5p were significantly higher than those of miR-21-3p in breast tumors from cohort 1 (p=2.2e−10). However, only miR-21-3p was more highly expressed in tumors than normal breast tissue (p=0.003), and in all three cohorts there was a strong positive correlation between MIR21 copy number and miR-21-3p expression levels. There was a significant higher expression of miR-21-3p in HER2 positive tumors compared to HER2 negative tumors in the two larger cohorts (p &lt; 0.05), and high miR-21-3p levels associated with higher histograde in the largest cohort (9.2e−14). A shorter breast cancer specific survival was associated with higher miR-21-3p expression in the METABRIC cohort (HR 1.338, CI 1.104-1.622, p=0.003). HER2 was the largest confounding factor but even after adjustment for HER2 positivity the effect remained significant (HR 1.260, CI 1.036-1.532, p = 0.021).
Our data show that miR-21-3p is expressed in breast tissue and tumors. Furthermore, our preliminary data suggest that miR-21-3p may be an indicator of worse outcome for breast cancer patients. However, additional work is needed to elucidate the association of miR-21-3p expression with distinct prognostic factors in breast cancer.
Citation Format: Arsalan Amirfallah, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th Johannsson, Bylgja Hilmarsdottir, Rosa Bjork Barkardottir, Inga Reynisdottir. miR-21-3p: A potential oncomir in breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3709.
Abstract 3717: LncRNA RNF157-AS1 inhibits autophagy in ovarian cancer cells by downregulating ARHI: The different role in proliferation and drug resistance
Authors: Xu Sujuan , Xu Pengfei 
Published: September 2020

Abstract
Ovarian cancer(OC) is the commonest cause of female cancer death. Long noncoding RNAs (lncRNAs) has been shown to have regulatory roles in the procession of many cancers, including OC. Here, in our previous study, we reported that lncRNA RNF157-AS1 was overexpression in OC tissues, which is confirmed by GSE144077 and TCGA matched GTEx normal data. Further experiments revealed that RNF157-AS1 knockdown significantly repressed the proliferation both in vitro and in vivo and overexpressed RNF157-AS1 promoted the proliferation of OC cells. However, the higher expression of RNF157-AS1 predicted a better prognosis for OC patients in TCGA database. RNA-seq analysis revealed that ARHI was significant overexpressed after RNF157-AS1 silencing and it is negative correlated with RNF157-AS1 in TCGA and matched GTEx normal data. ARHI, a autophagy-related gene, could induced autophagy in OC cells. Because of 70% of OC patients were diagnosed with advanced tumors and need to chemotherapy. Overexpression of RNF157-AS1 could inhibit autophagy-associated cell death and promote rapid proliferation of OC cells, while overexpressed RNF157-AS1 decrease autophagy and induced cells apoptosis under adverse environment. To test our hypothesis, CCK8 assay suggested overexpression of RNF157-AS1 significantly decreased the chemoresistance to cisplatin (DDP) and silencing of RNF157-AS1 increased the DDP-resistance of OC cells, which are confirmed by clone formation assay and apoptosis experiments. Western blot assay also suggested that RNF157-AS1 silencing promote ARHI, LC3II/I and beclin1 expression. To our knowledge, this is the first report revealed that the different roles of RNF157-AS1 in OC cells' proliferation and chemoresistance and our study also can provide guidance for clinical treatment of OC patients.
Citation Format: Sujuan Xu, Pengfei Xu. LncRNA RNF157-AS1 inhibits autophagy in ovarian cancer cells by downregulating ARHI: The different role in proliferation and drug resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3717.
Abstract 3731: Targeting the isocitrate dehydrogenase 1 (IDH1) metabolic enzyme in prostate cancer
Authors: Gonthier Kevin , Weidmann Cindy , Frégeau-Proulx Lilianne , Audet-Walsh Étienne 
Published: September 2020

Abstract
Prostate cancer cells (PCa) are dependent on the androgen receptor (AR) for their aberrant proliferation and survival. We have recently discovered that AR induces a reprogramming of PCa cell metabolism by controlling the cytoplasmic wild-type enzyme isocitrate dehydrogenase 1 (IDH1), which results in an enhanced proliferation of tumour cells. However, the specific metabolic functions of IDH1 in PCa or how to use the reliance of tumour cells on this enzyme as a therapeutic avenue, is elusive. In in vitro human PCa models, we showed that IDH1 protein levels and activity are increased in an AR-dependent manner. Using pharmacological and genetic tools, we showed that IDH1 is a major contributor to the replenishment of NADPH levels in PCa. This cofactor plays a key role in the synthesis of biomaterials required for cellular division, and our results indicate that IDH1 contribute to 30-40% of total cellular NADPH levels. In that context, blockade of IDH1 was shown to alter the mTOR signaling, a central regulator of cellular anabolism, which is linked to decreased cellular proliferation rates. FDA-approved pharmacological inhibitors of mutant IDH1 significantly inhibited IDH activity and proliferation in PCa cells, suggesting that such inhibitors could be used to treat PCa patients even in absence of IDH1 mutation. Globally, our results demonstrate that IDH1 is a key player in proliferative anabolic pathways in PCa. Importantly, they also support the hypothesis that inhibition of IDH1 using already-approved molecules represents one viable therapeutic solution.
Citation Format: Kevin Gonthier, Cindy Weidmann, Lilianne Frégeau-Proulx, Étienne Audet-Walsh. Targeting the isocitrate dehydrogenase 1 (IDH1) metabolic enzyme in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3731.
Abstract 3734: Expression of serine synthetic enzymes alters the sensitivity of ER-positive breast cancer cells to tamoxifen
Authors: Metcalf Stephanie , Kruer Traci , Dougherty Susan , Wittliff James L. , Klinge Carolyn M. , Clem Brian F. 
Published: September 2020

Abstract
Estrogen receptor positive breast cancer (ER+BC) is the most common form of breast cancer accounting for 65-75% of all diagnoses, yet, due to the availability of targeted therapies, has the best overall survival outcomes. However, it is estimated that up to 30% of all patients develop resistance to these therapies, resulting in recurrence or disease progression. Phosphoserine aminotransferase 1 (PSAT1), which is an enzyme within the serine synthetic pathway (SSP), has previously been implicated in endocrine resistance. Therefore, we sought to determine if there was a functional correlation between expression of PSAT1 or other serine synthetic enzymes and sensitivity to 4-hydroxytamoxifen (4-OHT) treatment. To investigate the correlation between PSAT1, another SSP enzyme phosphoglycerate dehydrogenase (PHGDH), and endocrine resistance, we examined clinical data from ER+ patients who received tamoxifen as their sole endocrine therapy. Using two separate cohorts, we confirmed that higher PSAT1 and PHDGH expression negatively correlates with poorer outcomes in tamoxifen treated ER+ BC patients. Next, we found that SSP enzyme expression and serine synthesis are elevated in tamoxifen resistant compared to tamoxifen-sensitive ER+ BC cells in vitro. To determine relevance to endocrine sensitivity, we modified the expression of both PSAT1 or PHGDH in each cell type. While overexpression of PSAT1 in tamoxifen-sensitive MCF-7 cells diminished 4-OHT inhibition, conversely, silencing of PSAT or PHGDH resulted in decreased proliferation in tamoxifen-resistant LCC9 treated with 4-OHT. Taken together, we postulate that overexpression of SSP enzymes appear to contribute to tamoxifen resistance in ER+BC and indicate a potential combinatorial therapeutic option.
Citation Format: Stephanie Metcalf, Traci Kruer, Susan Dougherty, James L. Wittliff, Carolyn M. Klinge, Brian F. Clem. Expression of serine synthetic enzymes alters the sensitivity of ER-positive breast cancer cells to tamoxifen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3734.
Abstract 3755: PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon cancer
Authors: Moench Romana , Gasser Martin , Nawalaniec Karol , Grimmig Tanja , Cao Minghua , Luo Yueming , Hsiao Li-Li , Waaga-Gasser Ana Maria 
Published: September 2020

Abstract
Anti-Epithelial/Vascular Endothelial Growth Factor (EGF/VEGF)-targeted therapy plays important roles in advanced stage colorectal cancer (CRC) patients but fails to show clinical efficacy in specific subgroups which lack of clear underlying mechanisms. In vitro studies indicated that cross-talk or alternative receptor/ligand activities can bypass anti-growth factor signaling arrest and therefore may explain failure of monoclonal antibody (mAb) targeted therapy. In this study we analyzed effects of Platelet Derived Growth Factor (PDGF)-mediated bypassed signaling in CRC. We first investigated human UICC (Union for International Cancer Control ) stage I-IV tumors (n=46) from our Center and found increased PDGFRβ and VEGFR1/2 gene expression (p&lt;0.01/p&lt;0.001). Interestingly, further analysis on human HT29 colon cancer in vitro showed upregulated VEGFR1/2 expression upon VEGF stimulation. This was even more pronounced upon stimulation with PDGF. Inhibition of VEGFR2 and EGFR resulted in decreased HT29 cell proliferation, while additional treatment with VEGF and particularly PDGF attenuated the inhibiting effect and resulted in altered downstream signaling events. Treatment with the tyrosine kinase inhibitor Regorafenib alone, that blocks VEGFR/EGFR+PDGFR, prevented PDGF and VEGF-induced proliferation. This effect was not observed for either VEGFR2 mAb treatment with Ramucirumab or EGFR mAb therapy with Cetuximab. To conclude, PDGF-induced human colon cancer proliferation in the absence of PDGFR and simultaneously inhibited VEGFR2 and EGFR expression in HT29 colon cancer cells suggests bypassed alternative PDGF receptor partners for ligand binding on the tumor cell surface and subsequent intracellular signaling. This may explain failure of anti-VEGF/EGF-targeted monoclonal antibody therapies in CRC patient subgroups and underlines the necessity to effectively inhibit PDGF-mediated signaling events beside VEGF/EGF blockade in patients with increased PDGF expression within their tumors.
Citation Format: Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser. PDGF-induced tumor cell growth despite VEGF/EGF inhibition and absence of PDGF receptor expression in colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3755.
Abstract 3765: c-Kit mediated phosphorylation of Spred1 regulates Neurofibromin-Spred1 interaction
Authors: Lorenzo Claire , Young Lucy C. , Tannka Alexandra , Urisman Anatoly , McCormick Frank 
Published: September 2020

Abstract
Spred1 negatively regulates Ras/MAPK signaling following growth factor stimulation. Spred1 inhibits Ras by binding and localizing Neurofibromin, a RasGAP, to the plasma membrane to accelerate Ras GTPase activity. c-Kit, a receptor tyrosine kinase (RTK), is known to interact with Spred1 but the consequence of this interaction is unknown. Here we demonstrate that c-Kit signaling regulates Neurofibromin-Spred1 interaction. Stimulation with c-Kit ligand, SCF, results in a transient disruption in Neurofibromin-Spred1 binding which corresponds to increased Ras signaling, followed by restoration of Neurofibromin-Spred binding which corresponds to nearly basal levels of Ras signaling. Mass spectrometry analysis identified potential phosphorylation sites on Spred1 that correspond to the initial disruption and later restoration of Neurofibromin-Spred1 binding. Phosphomimetic and phosphodeficient mutants affect the interaction. Our findings provide a potential mechanism by which RTK signaling regulates negative feedback to allow transient activation and subsequent termination of Ras signaling.
Citation Format: Claire Lorenzo, Lucy C. Young, Alexandra Tannka, Anatoly Urisman, Frank McCormick. c-Kit mediated phosphorylation of Spred1 regulates Neurofibromin-Spred1 interaction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3765.
Abstract 3777: The role of IFITMs in maintaining glioma stem cells
Authors: Nita Erisa , Evers Bernard , Nekulova Marta , Morrison Gillian , Ball Kathryn 
Published: September 2020

Abstract
Glioblastoma (GBM), one of the most lethal and heterogeneous primary brain tumors, contains cellular hierarchies with both quiescent and self-renewing highly tumorigenic glioblastoma stem cells (GSCs). Cancer stem cells within the context of the brain likely contribute to a lack of progress in patient survival time as they appear to have an innate resistance to both chemotherapeutic drugs and radiotherapy. The aim of this study is to elucidate how constitutive expression of interferons (IFNs) and their downstream signalling pathways maintain GSCs thereby supporting treatment resistance and tumor reoccurrence. To understand the mechanism of action of a subset of IFN regulated genes, originally characterized as a signature for radiation and chemotherapy resistance (IRDS), a panel of patient derived glioma stem cells was generated and manipulated using CRISPR/Cas9 mediated gene-editing. Phenotypic changes in growth, viability and drug resistance were characterised in the edited cells and linked to molecular level events using transcriptomic and proteomic techniques. Using this approach, in conjunction with patient tissue analysis, signalling under basal as well as IFN-activated conditions was studied in the context of GSC status.
Immunohistopathology of a glioma tissue micro-array identified an increased expression of IFN induced transmembrane receptors (IFITMs), which co-localised with Nestin, around the blood vessels suggesting that IFITM positive cells were in the stem cell niche. Further analysis showed the presence of both IFITM1 and IFITM3 in GSCs and established that loss of IFITM function impacted on growth rate and cell cycle progression as well as treatment sensitivity. By using wild-type and gene-edited GSC to focus on the relationship between IFITM1 and IFITM3, we have compelling phenotypic and molecular evidence that IFN-induced changes in the localisation of IFITMs impact on the ability of stem cells to ‘escape' normal growth control mechanisms. Taking into consideration the constitutive expression of interferons in the tumor microenvironment, our study provides evidence that IFITMs regulate glioma stem cell self-renewal and are involved in maintaining a quiescent population which can escape chemotherapy.
Citation Format: Erisa Nita, Bernard Evers, Marta Nekulova, Gillian Morrison, Kathryn Ball. The role of IFITMs in maintaining glioma stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3777.
Abstract 3778: MBNL1 regulated alternative splicing of MAP2K7 promotes de-differentiation of cancer cells by activating JNK
Authors: Ray Debleena 
Published: September 2020

Abstract
Therapeutic targeting of cancer stem cells (CSCs) is key to relapse-free, lasting response to cancer treatment. Several strategies against CSCs are currently in various stages of clinical development. However, there is need for additional targets. Here, we demonstrate that MBNL1, an RNA binding protein, is a suppressor of cancer-stemness. RNAi mediated down-regulation of MBNL1 promotes tumor-initiation, self-renewal, migration and invasion by up-regulating CSC-specific splice-isoforms. Particularly, the up-regulation of MAP2K7Δexon2 splice-isoform activates JNK signaling and establishes a feedback loop that promotes cancer-stemness. Pharmacological inhibition of JNK reverses CSC phenotypes in MBNL1low/MAP2K7Δexon2high CSC-like cells and these cells also show enhanced susceptibility to JNK inhibition. Remarkably, MBNL1 is down-regulated and MAP2K7Δexon2 splice-isoform is up-regulated in several cancer types. Down-regulation of MBNL1 is correlated with poor survival in gastric, lung and breast adenocarcinoma. In triple negative breast cancer, which is a highly aggressive disease characterised by enrichment of CSC-like cells, low MBNL1 correlates with poor relapse-free and distant metastasis-free survival. Our work shows, low MBNL1 and consequently high MAP2K7Δexon2 expression, is a biomarker for cancer stemness, high JNK activity and enhanced susceptibility to JNK inhibition. Hence, we have identified a novel alternative splicing driven mechanism of cancer cell de-differentiation and have identified biomarkers that can prognosticate patients for JNKi as a strategy to target CSCs.
Citation Format: Debleena Ray. MBNL1 regulated alternative splicing of MAP2K7 promotes de-differentiation of cancer cells by activating JNK [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3778.
Abstract 3794: Mammary cancer stem cells promote an aggressive phenotype in letrozole resistant breast cancer
Authors: Gallegos Karen Melissa , Patel Jankiben , Walker Rashidra R. , Davidson A Michael , Davenport Ian R. , Tilghman Syreeta L. 
Published: September 2020

Abstract
Aromatase inhibitors (AI), like letrozole, are the first-line treatment for ER+ breast cancer in post-menopausal women. Despite widespread successful usage of letrozole, resistance to therapy, tumor relapse, and metastasis remain the principal causes of death for breast cancer patients. While there are no cures for AI-resistant breast cancer, previous reports demonstrate AI resistance is associated with hormone independence, increased growth factor signaling, enhanced cellular motility and the epithelial to mesenchymal transition (EMT). Given recent evidence suggesting a convergence of EMT and cancer stem cells (CSC) and their combined implications in endocrine resistance, we hypothesized that breast cancer stem cells contribute to letrozole resistant breast cancer cells by increasing cellular motility. To test this hypothesis, ovariectomized immunocompromised female mice were inoculated in the mammary fat pad with either MCF-7 cells stably transfected with the human aromatase gene that were long term letrozole-treated (LTLT-Ca) or letrozole sensitive, MCF-7 cells stably transfected with the human aromatase gene (AC-1). Afterwards, intratumoral putative CSC marker expression was assessed by immunohistochemistry. Results indicate LTLT-Ca tumors were CD44+/CD24+ while AC-1 tumors were CD44low/CD24low. Both cell lines were cultured either adherently (2D) or as mammospheres (3D) and CD44/CD24 protein expression was assessed by immunoblots. When both cell lines were cultured three dimensionally, they expressed higher levels of CD44 and CD24 compared to their adherent counterparts, with the most robust change occurring within the LTLT-Ca cells. In order to quantitate the breast cancer stem cell activity mammosphere formation assay was performed and LTLT-Ca cells formed mammospheres at a 3.4-fold higher index compared to AC-1 cells. Additionally, we performed targeted gene expression arrays and our results demonstrated decreased expression of genes involved in cell adhesion and tumor suppression (ie., E-cadherin, caveolin 1 and β catenin). Taken together our study demonstrated a strong correlation between AI resistance, increased cancer stem cell expression, an invasive phenotype that may be associated with a poor prognosis. This work was supported by an NIH grant awarded to SL Tilghman (1SC1GM125617).
Citation Format: Karen Melissa Gallegos, Jankiben Patel, Rashidra R. Walker, A Michael Davidson, Ian R. Davenport, Syreeta L. Tilghman. Mammary cancer stem cells promote an aggressive phenotype in letrozole resistant breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3794.