bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B38: The role of BQ323636.1, a novel splice variant of NCOR2, in modulation of oxidative stress in breast cancer
Authors: Leung Man Hong , Tsoi Ho , Man Ellen Pui Sum , Lam Eric Wing-Fai , Khoo Ui Soon 
Published: August 2018

Abstract
Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) plays an important role in the signaling pathways governing survival and proliferation of breast cancer cells. Several chemotherapeutic drugs, such as taxanes, platinum compounds, and anthracyclines, induce cell death by enhancing the levels of ROS. Nuclear factor erythroid 2-related factor 2 (NRF2) is the master transcription factor regulating antioxidative responses against ROS. Overexpression of NRF2 has been found in breast cancer and it modulates oxidative stress response, leading to drug resistance in cancers. Our previous splice array study identified a novel splice variant of NCOR2, BQ323636.1 (BQ), as predictor of tamoxifen resistance in breast cancer. In the current study, we show overexpression of BQ could promote cell proliferation and protect cells from oxidative stress. In addition, overexpression of BQ could reduce the levels of ROS in breast cancer cells. We therefore hypothesized that BQ could compromise oxidative stress via the NRF2 pathway. By qPCR assay, several downstream targets of NRF2 were found to be upregulated in BQ-overexpressing cells. This suggested that NRF2 transcriptional activity could be modulated by BQ. The results from luciferase reporter assay confirmed that NCOR2 could repress the transcriptional activity via antioxidant response element (ARE), the primary binding site of NRF2 in promoter region. BQ could reverse the repressive effect of NCOR2 on ARE, suggesting that BQ might modulate NRF2 activity via NCOR2. Co-immunoprecipitation indicated NCOR2 interacted with NRF2. BQ overexpression might inhibit such an interaction. Taken together, our results suggest that BQ regulates NRF2 signaling pathway via interfering with NCOR2 activity. Our findings reveal a novel role for BQ as a modulator of NRF2 and oxidative stress in breast cancer.
Citation Format: Man Hong Leung, Ho Tsoi, Ellen Pui Sum Man, Eric Wing-Fai Lam, Ui Soon Khoo. The role of BQ323636.1, a novel splice variant of NCOR2, in modulation of oxidative stress in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B38.
Abstract B41: BP1 is an important biomarker in breast cancer
Authors: Berg Patricia E. , Man Yan-gao , Simmens Samuels , Fu Sidney W. , Cavalli Lucianne , Vesuna Farhad , Kirolikar Saurabh , Schwartz Arnold 
Published: August 2018

Abstract
Beta protein 1 (BP1), a transcription factor (TF) we identified and cloned, is encoded by a homeobox gene called DLX4. BP1 is overexpressed in breast cancer, prostate cancer, ovarian cancer, acute myeloid leukemia, non-small cell lung cancer, and possibly other malignancies as well. Important characteristics of BP1 in breast cancer, a focus in our laboratory, include findings that: (1) BP1 is expressed in 80% of invasive ductal breast tumors, including 89% of the tumors of African American women. These data are based on both RNA and protein data. (2) BP1 expression correlates with the progression of breast tumors, from 0% in normal breast tissue to 21% in hyperplasia and 46% in ductal carcinoma in situ. (3) BP1, which maps to 17q21, can be activated by DNA amplification. (4) BP1 appears to be associated with metastasis. Forty-six cases of inflammatory breast cancer were examined; all were positive for BP1 expression. Nine cases had metastasized; lymph nodes from all nine were also BP1 positive. Moreover, BP1 activates a known trigger of metastasis, the Twist gene. (5) BP1 overexpression induces oncogene expression. BP1 activates the BCL-2 gene; high BCL-2 protein levels are associated with resistance to drug and radiation therapy. BP1 also activates VEGF and c-MYC, as well as other genes important in angiogenesis, invasion, and metastasis. (6) Cells overexpressing BP1, when injected into the fat pads of nude mice, were associated with larger and more frequent tumors than found in control mice receiving cells with low BP1. In summary, BP1 appears to confer properties on breast cancer cells that lead to a more invasive and aggressive phenotype. Since the functions of homeotic transcription factors are highly conserved, it is possible that BP1 regulates many of the same processes and genes in other malignancies in which it is active.
Citation Format: Patricia E. Berg, Yan-gao Man, Samuels Simmens, Sidney W. Fu, Lucianne Cavalli, Farhad Vesuna, Saurabh Kirolikar, Arnold Schwartz. BP1 is an important biomarker in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B41.
Abstract IA14: Breast tumor evolution: The role of the microenvironment
Authors: Polyak Kornelia 
Published: August 2018

Abstract
The immune system and the tissue microenvironment shape tumor evolution by providing selection for cancer cells with certain phenotypes. Immunotherapy is one of the most promising current cancer therapies and one of the very few that has the potential to cure even advanced metastatic disease. However, in breast cancer its success thus far has been limited to a subset of triple-negative tumors. This could be due to the testing of a limited set of immune-regulatory agents, but also a consequence of heterogeneity among tumors for mechanisms by which they escape immune surveillance. We hypothesized that the in situ to invasive carcinoma transition is a critical step for immune escape in breast cancer, since in DCIS (ductal carcinoma in situ) cancer cells are still physically separated from the stroma by the basement membrane and myoepithelial cell layer, and tumor-infiltrating leukocytes are rarely detected in direct contact with cancer cells. In contrast, in invasive tumors cancer cells and leukocytes are mixed, providing a strong selection for cancer cells that can overcome a potential immune attack. To begin dissecting mechanisms of immune escape during breast tumor evolution, we analyzed the composition of leukocytes in normal breast tissues, DCIS, and invasive ductal carcinomas (IDC) by a combination of technologies including FACS, RNA-seq, multicolor immunofluorescence, and immune-FISH. Based on these analyses, we found that invasive tumors have a less active immune environment due to a combination of upregulation of immune-suppressive mechanisms by both the cancer cells and various other cell types composing the microenvironment. Our results will improve our understanding of immune escape in breast cancer and aid the design of more effective immunotherapies for both advanced and early-stage disease.
Citation Format: Kornelia Polyak. Breast tumor evolution: The role of the microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA14.
Abstract IA19: Homologous recombination repair deficiency and breast cancer progression in high-risk populations
Authors: Olopade Olufunmilayo I. 
Published: August 2018

Abstract
Analysis of cancer genomes has rapidly become an integral part of the practice of clinical oncology, with implications for diagnosis, prognosis, treatment, and prevention. Inherited and sporadic cancers often share common mutational events. When inherited mutations are identified, genetic counseling is an essential component of care. Pathogenic BRCA1 and BRCA2 mutations are the strongest predictors of breast cancer risk and may be the strongest predictors of other inherited forms of solid tumors and hematologic malignancies as well. Waiting to treat advanced breast cancer with targeted therapies is a failure of primary prevention, and population-based strategies for risk management in high-risk populations will be needed. Understanding breast cancer progression in genetic defined subgroups has the potential to accelerate progress in precision medicine. I will discuss ongoing research in our group, our recent findings in defining the genomic landscape of early-onset breast cancer, and future directions for the early detection, treatment, and prevention of breast cancer in high-risk populations.
Citation Format: Olufunmilayo I. Olopade. Homologous recombination repair deficiency and breast cancer progression in high-risk populations [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA19.
Abstract 02: BCL-W significantly contributes to B-cell lymphoma survival and development
Authors: Adams Clare M. , Mitra Ramkrishna , Gong Jerald Z. , Kim Annette S. , Choi John K. , Eischen Christine M. 
Published: August 2018

Abstract
The ability of cells to undergo apoptosis in response to cellular stresses functions as a safeguard against tumorigenesis. Consequently, compromised apoptotic signaling must precede tumor development. To design effective therapies for cancer treatment, the underlying mechanisms that govern cell survival need to be understood. The anti-apoptotic proteins of the Bcl-2 family are key regulators of cell survival and are frequently overexpressed in malignancies, leading to increased cancer cell survival. Bcl-w, the closest anti-apoptotic relative to Bcl-2 and Bcl-xL, is essential for spermatogenesis, but was considered dispensable for other cell types. However, we recently uncovered a significant role for Bcl-w in B-cell survival and lymphomagenesis. Specifically, loss of Bcl-w conferred sensitivity to growth factor deprivation-induced B-cell apoptosis. In addition, apoptosis triggered by hyperproliferative signals from the Myc oncogene was accentuated by loss of Bcl-w. Consequences of elevated apoptosis were observed in vivo, as Bcl-w loss profoundly delayed Myc-mediated B-cell lymphoma development. We also determined Myc regulates Bcl-w expression through its transcriptional regulation of the miR-15 family. Importantly, evaluation of Burkitt lymphoma (BL) patient samples revealed BCL-W overexpression was highly selected for, and that targeting BCL-W using multiple methods induced apoptosis of BL cells. In addition, overexpression of BCL-W in BL cell lines conferred resistance to the BH3-mimetics ABT-737 and ABT-263 that inhibit anti-apoptotic BCL-2 family members. Furthermore, BCL-W was overexpressed in diffuse large B-cell lymphoma (DLBCL) and correlated with decreased patient survival. Analysis of multiple data sets of other aggressive and indolent B-cell lymphomas showed that BCL-W was frequently overexpressed in them as well. Collectively, our data indicate that BCL-W is an understudied contributor to B-cell lymphoma development and survival that appears to be as important as BCL-2 to B-cell lymphomas. In addition, BCL-W is a predictive biomarker that could improve prognostication and the development of more effective treatment strategies for B-cell lymphomas.
Citation Format: Clare M. Adams, Ramkrishna Mitra, Jerald Z. Gong, Annette S. Kim, John K. Choi, Christine M. Eischen. BCL-W significantly contributes to B-cell lymphoma survival and development [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 02.
Abstract IA01: Mechanisms of formation and progression of preleukemic stem cells
Authors: Steidl Ulrich 
Published: August 2018

Abstract
Relapse continues to be the most common cause of death in AML and overall cure rates remain low. Recent evidence has shown that the accumulation of stepwise genetic and epigenetic changes in HSC lead to the formation of precancerous/preleukemic stem cells (pre-LSC) that play a pivotal role not only in disease origination but also in leukemia relapse. While the existence and essentiality of such precancerous cell states has been demonstrated in mice and humans, still very little is known about the molecular mechanisms driving pre-LSC formation and progression. We have recently performed molecular studies of pre-leukemic cell states in mouse genetic models as well as primary cells from patients, and discovered new transcription factors and regulatory mechanisms in pre-LSC in MDS and AML. Specifically, we discovered critical roles for several nonclustered homeobox transcription factors in pre-LSC, and identified functionally critical and pharmacologically targetable downstream effectors. We also found that enhancer haplodeficiency and consequent minimal reduction of key transcription factors is sufficient to induce pre-LSC formation and subsequent progression to MDS and AML. Such models provide novel tools for mechanistic study of pre-LSC and their progression to overt MDS and AML, and for the development and testing of pharmacologic approaches to therapeutically interfere with these processes.
In summary, recent studies have started to shed light on preleukemic cell states as the earliest origin of MDS and AML, as well as molecular mechanisms driving their formation and progression, which provides a basis for their specific therapeutic targeting for causative treatment of MDS and AML.
Citation Format: Ulrich Steidl. Mechanisms of formation and progression of preleukemic stem cells [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA01.
Abstract IA10: Targeted therapies as molecular probes for comprehensive preclinical evaluation
Authors: Dawson Mark A. 
Published: August 2018

Abstract
Cancer biology is profoundly influenced by changes in the epigenome. Because the dynamic plasticity of the epigenome lends itself well to therapeutic manipulation, the past few years have witnessed an unprecedented investment in the development, characterization, and translation of targeted epigenetic therapies. Several of these epigenetic therapies have now transitioned into the clinical arena, and emerging evidence suggests that these drugs are well tolerated and show single-agent efficacy in a range of hematopoietic cancers. The enduring challenge for clinicians and scientists will be understanding the cellular and molecular mechanisms that may govern sensitivity and resistance to these agents. This information could then be used to design more effective combination regimes. A major limitation to our current knowledge is the fact that we are blinded to the mechanism of action of these agents in a cellular context. In this seminar, I will discuss our strategy to overcome this limitation by converting epigenetic agents into molecular probes that maintain the functional integrity of the compound but now allow the compounds to be used much like antibodies in all routine cell and molecular assays both in vitro and in vivo.
Citation Format: Mark A. Dawson. Targeted therapies as molecular probes for comprehensive preclinical evaluation [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA10.
Abstract IA31: Targeting immune receptor mutations in lymphoma
Authors: Wendel Hans-Guido 
Published: August 2018

Abstract
The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as “micropharmacies” able to deliver an anticancer protein.
Citation Format: Hans-Guido Wendel. Targeting immune receptor mutations in lymphoma [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA31.
Abstract PR02: Mechanisms of NT5C2 activating mutations driving thiopurine resistance in relapsed lymphoblastic leukemia
Authors: Dieck Chelsea L. , Tzoneva Gannie , Forouhar Farhad , Carpenter Zachary , Sanchez-Martin Marta , Ambesi-Impiombato Alberto , Kirschner-Schwabe Renate , Lew Scott , Seetharaman Jayaraman , Tong Liang , Ferrando Adolfo 
Published: August 2018

Abstract
Activating mutations in cytosolic 5'-nucleotidase II (NT5C2) drive resistance to 6-mercaptopurine (6-MP) in relapsed acute lymphoblastic leukemia (ALL). These gain-of function alleles encode proteins with increased nucleotidase activity, yet their specific molecular mechanisms are poorly understood. Allosteric activation of NT5C2 is primarily mediated by a marked conformational change in the helix A region, which reconfigures the catalytic center for substrate access and catalysis. Here we demonstrate that constitutively active NT5C2 mutant proteins (K359Q and L375F) adopt active helix A region structures in the absence of allosteric activator. Moreover, crystallographic, structural modeling, genetic, and functional antibody analyses identify a switch-off mechanism mediated by the dynamic mobilization of Asp407 in the tip region of the arm segment which, guided by positively charged residues located in the surface of a basic inter-monomeric cavity exposed upon allosteric activation, turns off NT5C2 by interacting with and disrupting the helical conformation of helix A. Loss of this regulatory mechanism in NT5C2 mutants involving the tip region of the arm segment and the inter-monomeric cavity drives increased nucleotidase activity and allosteric response. Finally, increased allosteric activation by the Q523X mutation results from loss of the NT5C2 C-terminal acidic tail segment, which promotes a closed inactive state in basal conditions. These results uncover dynamic mechanisms responsible for NT5C2 regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.
This abstract is also being presented as Poster 05.
Citation Format: Chelsea L. Dieck, Gannie Tzoneva, Farhad Forouhar, Zachary Carpenter, Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Renate Kirschner-Schwabe, Scott Lew, Jayaraman Seetharaman, Liang Tong, Adolfo Ferrando. Mechanisms of NT5C2 activating mutations driving thiopurine resistance in relapsed lymphoblastic leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr PR02.
Abstract A02: Investigating the contribution of RAD51 paralog mutations to cancer development
Authors: Baldock Robert A. , Pressimone Catherine A. , Bernstein Kara A. 
Published: August 2018

Abstract
Homologous recombination (HR) is a high-fidelity DNA repair mechanism that utilizes a homologous template to repair double-strand breaks (DSBs). The defining step of HR is the formation of a RAD51 nucleoprotein filament, which performs the homology search and strand invasion steps. RAD51 filament formation is aided by the RAD51 paralogs, which structurally resemble RAD51. The RAD51 paralogs form sub-complexes including CX3 (RAD51C and XRCC3) and BCDX2 (RAD51B, RAD51C, RAD51D, and XRCC2).
Here we use a use a Yeast 3-hybrid assay to determine which patient-identified mutations in RAD51D impair the interaction with RAD51C and XRCC2. We further validate this interaction data in mammalian cells. Lastly, we are going to complement RAD51D and XRCC2-depleted cells with mutant versions of the proteins to determine their impact on HR as well as sensitivity to specific chemotherapeutic agents.
Citation Format: Robert A. Baldock, Catherine A. Pressimone, Kara A. Bernstein. Investigating the contribution of RAD51 paralog mutations to cancer development. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A02.
Abstract A08: A novel system determines the functional significance of ovarian tumor mutations in the homologous recombination gene RAD51C
Authors: Sullivan Meghan R. , Prakash Rohit , Mihalevic Michael J. , Baird Jared M. , Jasin Maria , Bernstein Kara A. 
Published: August 2018

Abstract
Homologous recombination (HR) deficiency is associated with hereditary ovarian carcinomas. HR deficiency can occur through somatic and germline mutations in BRCA1, BRCA2, and other associated genes such as RAD51C. Understanding the impact of HR gene mutations on DNA double-strand break (DSB) repair is critical for developing targeted therapeutic strategies for these patients. Although BRCA1 and BRCA2 deficiency has been well characterized, limited functional analysis has occurred in patients harboring mutations in RAD51C. RAD51C mutations are found in familial breast and ovarian cancers and in Fanconi anemia-like syndrome, FANCO. To determine which RAD51C-tumor associated mutations disrupt HR, we utilized a novel RAD51C conditional knockout breast epithelial cell line (MCF10A) generated by Dr. Maria Jasin. In collaboration with the Jasin laboratory, we complemented these cells with RAD51C and RAD51C cancer-associated mutants. Using yeast-two-hybrid and co-immunoprecipitation strategies, we identified RAD51C mutations that disrupt RAD51C protein-protein interactions. For example, we identified RAD51C mutations that impair RAD51C interaction with either its binding partner RAD51B, RAD51D, or XRCC3. We next measured RAD51C mutant cells for viability and HR proficiency at an I-SceI-induced DSB using a DR-GFP reporter assay. We identified RAD51C mutations that impact HR repair, suggesting that patients harboring these mutations would be good candidates for PARPi. Our goal is to identify specific RAD51C mutations that disrupt HR to predict which RAD51C-deficient tumors will respond to therapy.
Citation Format: Meghan R. Sullivan, Rohit Prakash, Michael J. Mihalevic, Jared M. Baird, Maria Jasin, Kara A. Bernstein. A novel system determines the functional significance of ovarian tumor mutations in the homologous recombination gene RAD51C. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A08.