bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B28: Activating mutations in PIK3CB confer resistance to PI3K inhibition in PTEN-deficient breast cancer and define a novel oncogenic role for p110β
Authors: Nakanishi Yoshito , Walter Kimberly M. , Spoerke Jill M. , O'Brien Carol , Huw Ling Y. , Hampton Garret M. , Lackner Mark R. 
Published: May 2016

Abstract
Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs commonly in breast cancers via mechanisms that include loss of function of the tumor suppressor phosphatase and tensin homolog (PTEN). Experience with other successful targeted agents suggests that clinical resistance to PI3K inhibitors is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN deficient breast cancers. PTEN null breast cancer cell lines were selected for resistance to a pan-PI3K inhibitor, GDC-0941. Comprehensive molecular and cellular profiling was conducted to identify the mechanism of resistance. We generated GDC-0941 resistant derivatives of PTEN deficient EVSA-T and ZR-75-1 cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines. We found that the PIK3CB mutation at D1067 position was recurrent in cancer patients. Stable expression of mutant PIK3CB variants in PTEN null breast cancer cells conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. We showed further that the p110β D1067Y mutant is highly activated and elevates PIP3 level at the cell membrane, promoting localization and activation of AKT and PDK1 at the cell membrane and driving PI3K signaling to a level that can overcome treatment with proximal inhibitors. Finally, we show that the PIK3CB D1067Y mutant can behave as an oncogene and transform normal cells, and that PTEN knock down enhances this activity. These novel preclinical and clinical findings implicate PIK3CB D1067 alterations as a novel oncogene that may cause resistance to selective PI3K inhibitor treatment. Taken together with previous findings that PTEN deficient cancers tend to signal through p110β rather than p110α, this work also suggests PTEN deficient breast cancers may depend on p110β and are thereby susceptible to PIK3CB mutation as an escape mechanism from PI3K inhibition.
Citation Format: Yoshito Nakanishi, Kimberly M. Walter, Jill M. Spoerke, Carol O'Brien, Ling Y. Huw, Garret M. Hampton, Mark R. Lackner. Activating mutations in PIK3CB confer resistance to PI3K inhibition in PTEN-deficient breast cancer and define a novel oncogenic role for p110β. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B28.
Abstract PR02: The spliceosome is a therapeutic vulnerability in MYC-driven breast cancer
Authors: Hsu Tiffany , Simon Lukas , Neill Nicholas , marcotte richard , Sayad Azin , Karlin Kristen , Lagisetti Chandraiah , Cooper Thomas , Webb Thomas , Neel Benjamin , Shaw Chad , Westbrook Thomas (“Trey”) 
Published: May 2016

Abstract
c-MYC (MYC) hyperactivation is one of the most common drivers of human breast cancer and correlates with poor prognosis. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto breast cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We demonstrate that core components of the spliceosome and its catalytic activity are required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces global changes in mRNA metabolism and increases the burden on the core spliceosome to process pre-mRNA. In primary human breast cancers, MYC hyperactivation is associated with altered splicing efficiency. In contrast to normal mammary epithelium, partial inhibition of the spliceosome in MYC-hyperactivated breast cancers leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome are therapeutic entry points for aggressive MYC-driven breast cancers.
Citation Format: Tiffany Hsu, Lukas Simon, Nicholas Neill, richard marcotte, Azin Sayad, Kristen Karlin, Chandraiah Lagisetti, Thomas Cooper, Thomas Webb, Benjamin Neel, Chad Shaw, Thomas (“Trey”) Westbrook. The spliceosome is a therapeutic vulnerability in MYC-driven breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr PR02.
Abstract A02: A kinome-wide RNAi screen in Drosophila glia and human GBM models reveals Stk17A drives neoplastic glial proliferation and migration
Authors: Wardwell-Ozgo Joanna , Mosley Colleen , Kornblum Harley , Read Renee 
Published: May 2016

Abstract
Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, are highly proliferative, diffusely invasive, and incurable by current therapies. Genetic and molecular analyses reveal that GBMs frequently harbor activating mutations in the EGFR receptor tyrosine kinase (EGFR) and Pi-3 kinase (PI3K) signaling pathways. While the ability of these mutations to drive gliomagenesis has been verified in mouse models, current data also indicate that EGFR and PI3K signaling cooperates with as yet unknown factors to drive its invasive pathology and therapeutic resistance in GBM. To identify such factors, we performed a cross-species, multidisciplinary genetic screen in both Drosophila melanogaster and mammalian GBM model systems designed to identify novel genes that augment EGFR- and PI3K- dependent neoplasia.
Our results in both Drosophila and GBM cell culture and animal model systems indicate that Stk17A, a cytoplasmic serine-threonine kinase subject to copy-gain and overexpression in GBM, is necessary for GBM cell proliferation and invasion. Our data also illustrate that overexpression of Stk17A in combination with oncogenic EGFR mutations is sufficient to promote increased glial cell proliferation and invasion. Furthermore, in our GBM model systems, we find that Stk17A overexpression stimulates increased phosphorylation and activity of non-muscle myosin II regulatory light chain (MRLC), a known Stk17A substrate and key regulator of the cell cycle and cellular motility, which itself is required for neoplastic glial transformation. Finally, oncogenomic analysis of GBMs and other high-grade gliomas reveal that Stk17A becomes overexpressed in association with EGFR-PI3K mutations, and Stk17A copy-gain and overexpression are significantly associated with poor prognosis in patients.
Together, these mechanistic insights indicate that Stk17A potentiates the oncogenenic effects of EGFR- and PI3K-driven tumors through the upregulation of MLRC activity, and suggest that Stk17A may serve as a novel therapeutic target for EGFR-PI3K dependent GBMs and high-grade gliomas. Current work is continuing to examine the molecular function of Stk17A in the context of GBM, normal glia, and neural stem cells in order to further our understanding of how Stk17A contributes to tumor pathology.
Citation Format: Joanna Wardwell-Ozgo, Colleen Mosley, Harley Kornblum, Renee Read. A kinome-wide RNAi screen in Drosophila glia and human GBM models reveals Stk17A drives neoplastic glial proliferation and migration. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A02.
Abstract B22: Analysis of Lgr5-positive cells in mouse mammary gland
Authors: Zhang Lixing , Howe Louise , Kolesnick Richard , Brown Anthony 
Published: May 2016

Abstract
Lgr5 has been identified as a stem cell marker in multiple adult tissues, and individual Lgr5+ mammary epithelial cells are capable of regenerating mouse mammary glands in transplantation assays. Here we investigated the proliferation and differentiation capabilities of murine mammary Lgr5+ cells in vitro, and their distribution in mouse mammary glands in vivo. Equal numbers of sorted Lgr5+ and Lgr5- epithelial cells were cultured in Matrigel to evaluate their stem-like properties in vitro. Compared with Lgr5- cells, Lgr5+ cells were more efficient at generating organoids in 3D culture, and the Lgr5+ cell-derived organoids grew to a larger size. Moreover, Lgr5+ cell-derived organoids survived repeated passaging and contained cells of both luminal and basal lineages, as indicated by keratin marker expression. Incidence of Lgr5+ cells in organoids was confirmed by in situ hybridization. These studies indicate that Lgr5+ cells retain the self-renewal and differentiation capabilities of stem cells ex vivo. The in vivo distribution of Lgr5+ cells was investigated using X-Gal-stained mammary glands from Lgr5-lacZ reporter mice ranging from 5 to 32 weeks old. In both adolescent and adult mice, we observed a graded distribution of Lgr5+ cells with greater abundance in the nipple-proximal (ventral) ducts than in the lymph-node proximal central region, and fewest Lgr5+ cells in the distal (dorsal) region of the glands. Lgr5+ cells from all mammary gland regions appeared capable of yielding organoids in culture. These results corroborate in organoid culture the known stem-like properties of Lgr5+ cells defined in intact mouse mammary gland.
[Supported by NIH grant CA186981 and the China Scholarship Council]
Citation Format: Lixing Zhang, Louise Howe, Richard Kolesnick, Anthony Brown. Analysis of Lgr5-positive cells in mouse mammary gland. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B22.
Abstract B30: Regulation of proliferation and differentiation by atonal homolog 1 phosphorylation
Authors: Tomic Goran , Winton Douglas J. , Philpott Anna 
Published: May 2016

Abstract
Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that acts as a tumor-suppressor as well as drives the differentiation of intestinal progenitor cells. Phosphorylation of Atoh1 is an important regulatory mechanism of its activity; proteins of the bHLH family can be phosphorylated by cyclin-dependent kinases during the cell cycle, which affects their differentiation-driving potential.
We generated a colon cancer cell line model to investigate site-specific phosphoregulation of Atoh1. A mutant Atoh1, which has multiple serine/threonine residues changed to alanine at serine-proline (SP) and threonine-proline (TP) sites (9S/T-A Atoh1), was generated and expressed in a doxycycline-inducible model at a single copy level. The loss of phosphorylation induced hyper-activation of Atoh1 with respect to differentiation and proliferation arrest; 9S/T-A Atoh1 inhibited proliferation more than the wild-type protein. Overexpression of Atoh1 caused G1 cell-cycle arrest. Atoh1 induced expression of the secretory lineage markers, while absorptive lineage markers were down regulated. Phospho-mutant protein was able to not only inhibit proliferation but also drive the differentiation of previously undifferentiated colon cancer cell line more strongly than the wild type protein.
Investigating the significance of phosphorylation of Atoh1 in the context of its tumor-suppressive role is of great importance in colon cancer. A better insight into the differentiation processes and their deregulation in cancer has the potential to open further avenues and introduce promising strategies in differentiation-targeted cancer therapies.
Citation Format: Goran Tomic, Douglas J. Winton, Anna Philpott. Regulation of proliferation and differentiation by atonal homolog 1 phosphorylation. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B30.
Abstract IA17: Dynamic changes in the epigenetic landscape during retinal development, cellular reprogramming, and tumorigenesis
Authors: Dyer Michael 
Published: May 2016

Abstract
The stepwise progression from proliferating multipotent progenitor cells to terminally differentiated neurons in the developing central nervous system (CNS) is marked by dramatic changes in gene expression programs. Those changes in gene expression are accompanied by changes in histone modifications at individual promoters, gene bodies and enhancers as well as changes in the higher order structure of the chromatin. Once established during development, the cell-type specific epigenome of differentiated cells is thought to be relatively stable. Indeed, one of the major barriers to reprogramming differentiated cells such as neurons into induced pluripotent stem cells (iPSCs) is the reversal of the epigenetic landscape that was established during differentiation. For some cell types, the cell-type specific epigenetic programs are not completely erased during reprogramming and the resulting induced pluripotent stem cells (iPSCs) retain an epigenetic memory of their cellular origins. The dynamic changes in the epigenome that occur during development are also important for human disease. Childhood cancers are developmental tumors that arise during critical periods of development across diverse tissues. In a childhood cancer of the developing retina called retinoblastoma, it was shown the epigenetic reprogramming is required for tumorigenesis and this led to the identification of a novel druggable target for this ocular tumor. However, it is not known if the epigenetic changes that accompany tumorigenesis in childhood cancer are similar to those that occur during cellular reprogramming or if it is a completely distinct process that is required for oncogenic transformation. In this presentation, I will compare and contrast the changes in the epigenome that accompany changes in gene expression during retinal development, retinal neuron reprogramming and in retinoblastoma to gain a deeper understanding of the epigenome in development and cancer.
Citation Format: Michael Dyer. Dynamic changes in the epigenetic landscape during retinal development, cellular reprogramming, and tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA17.
Abstract IA31: Control of TGF-β responsiveness and epithelial plasticity
Authors: Derynck Rik , Budi Erine , Muthusamy Baby-Periyanayaki , Katsuno Yoko , Du Dan 
Published: May 2016

Abstract
TGF-β signaling inhibits cell growth in epithelial cells and thus acts as tumor suppressor, yet increased TGF-β signaling often promotes cancer progression through effects on the tumor micro-environment and effects on the carcinoma cells that can lead to epithelial plasticity responses and increased invasion. The responsive epithelial or carcinoma cells can regulate their cell surface levels of TGF-β receptors, and thus enhance their responses to TGF-β. In addition to transcription control of TGF-β receptor expression, the cells can rapidly mobilize TβRII and TβRI from a large intracellular receptor pool to the cell surface, and thus enhance their TGF-β responsiveness. For example, high glucose, as seen in hyperglycemia, rapidly induces high levels of cell surface receptors that increase the cell’s TGF-β responsiveness, resulting in extracellular matrix production and increased cell size. Similarly, increased cell surface TGF-β receptor levels and TGF-β responsiveness also occur in response to insulin, which is therapeutically used against diabetes-associated hyperglycemia. The insulin-induced increase in cell surface levels requires activation of Akt, which then phosphorylates the membrane-associated RabGAP AS160, thus alleviating AS160-mediated retention of vesicles containing TβRII and TβRI, and allowing them to reach the cell surface. Additionally, the levels of functional TGF-β receptor complexes at the cell surface is controlled by TACE-mediated ectodomain shedding, which is activated in response to Erk and p38 MAPK activation. We will discuss the physiological implications of these multiple levels of control of TGF-β receptor cell surface presentation and TGF-β responsiveness in cancer cell behavior and cancer progression. Finally, the epithelial plasticity response to TGF-β is also controlled by the direct interaction of activated Smad3 with a methyltransferase, which consequently controls the histone modifications of the gene encoding the transcription factor Snail, a master regulator that drives epithelial-mesenchymal transition. Thus, Smad-mediated changes of histone methylation complement direct Smad-mediated transcription effects in the control of epithelial-mesenchymal transition.
Citation Format: Rik Derynck, Erine Budi, Baby-Periyanayaki Muthusamy, Yoko Katsuno, Dan Du. Control of TGF-β responsiveness and epithelial plasticity. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA31.
Abstract IA33: Regulation of TGF-β receptor signaling in cancer
Authors: Dijke Peter ten 
Published: May 2016

Abstract
TGF-β plays a crucial role during development and in maintaining tissue homeostasis. Perturbation in signaling via TGF-β type I and type II serine/threonine kinase receptors and intracellular SMAD transcriptional effectors, can lead to a large variety of diseases, including cancer. TGF-β has a dual role in cancer progression. During the early phase, TGF-β acts as a tumor suppressor, exemplified by deletions or mutations in the core components of the TGF-β signaling pathway. In late phase, TGF-β promotes processes that support tumor progression such as tumor cell invasion, dissemination, and immune evasion. Clinical trials for the treatment of cancer patients using systemic TGF-β signaling inhibitors have been initiated. These agents target TGF-β ligand or TGF-β receptor and inhibit all responses, and may have unwanted on-target effects. I will present our efforts to identify new druggable regulators of TGF-β signaling, which may allow for a more selective antagonism of the tumor promoting pathways by TGF-β. For example, E3 ubiquitin ligase TRAF4 and deubiquitinating enzyme USP4 - that are highly expressed in breast cancer - regulate the stability of specific TGF-β signaling components and thereby promote TGF-β-induced breast cancer cell invasion and metastasis.
Citation Format: Peter ten Dijke. Regulation of TGF-β receptor signaling in cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA33.
Abstract PR01: 3D enhancer clusters in the response to Wnt-driven colorectal cancer
Authors: Schuijers Jurian , Day Daniel S. , Saint-Andre Violaine , Young Richard A. 
Published: May 2016

Abstract
Super-enhancers are clusters of enhancers that drive expression of genes key to development and cancer. We recently showed that super-enhancers and their target genes occur within DNA loops bounded by CTCF proteins. These chromosome structures constrain the activities of enhancers to genes that occur within the same loop, and were thus called insulated neighborhoods. Recent studies have shown that signaling pathways converge on super-enhancers, but the effect of signaling-mediated gene activation has yet to be investigated in the context of insulated neighborhood structure and function. We used a model of Wnt-pathway activation in colon cancer to investigate Wnt-mediated activation of target genes within insulated neighborhoods. When the Wnt-pathway was activated through genetic deletion of the tumor suppressor Apc in intestinal organoids, all enhancers within insulated neighborhoods that contained Tcf4 binding sites were activated, including enhancers that were not considered to contribute to super-enhancers. Thus, Wnt-stimulation co-activated multiple enhancers that are not in linear proximity, yet cluster in 3D space within insulated neighborhoods. We conclude that insulated neighborhoods allow the formation of 3D enhancer clusters whose constituents can operate concertedly, and thus expand the definition of super-enhancers to incorporate 3D chromatin organization.
This abstract is also presented as Poster A15.
Citation Format: Jurian Schuijers, Daniel S. Day, Violaine Saint-Andre, Richard A. Young. 3D enhancer clusters in the response to Wnt-driven colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr PR01.
Abstract A10: SLC7A11 contributes to the pathogenesis of lung cancer
Authors: Ji Xiangming Ji , Qian Jun , Rahman Jamshedur , Harris Brad , Hoeksema Megan , Chen Heidi , Eisenberg Rosana , Young Jamey 
Published: May 2016

Abstract
Introduction: Many tumors increase uptake and dependence on nutrients such as glucose, cysteine or glutamine. These basic observations on cancer cell metabolism have opened multiple new diagnostic and therapeutic avenues in cancer. Here, we investigated the function of SLC7A11 (xCT), a cystine/glutamate anti-porter, in the pathogenesis of lung cancer. Recently, we found xCT to be strongly overexpressed at the cell surface of lung cancers and began to investigate the mechanisms by which xCT may contribute to lung cancer progression.
Methods: The expression of xCT and its related genes in 411 patients with non small cell lung cancer (NSCLC) were evaluated in publically available lung cancer gene expression datasets. The association between xCT expression and overall survival, stage of diseases were tested in tissue microarray datasets. Gain of function studies for xCT were undertaken in the normal airway epithelium cell lines (BEAS2B and 16HBE) to investigate the role of xCT in regulating cell metabolism, growth and survival in normal and malignant lung epithelial cells.
Results: Our results shows that xCT proein is overexpressed in 38% of NSCLC patients. We also found that expression of xCT mRNA is strongly associated with disease stage (p&lt;0.01), smoking history (p =0.0202) and overrall survival (p&lt;0.01). Overexpression of xCT in normal airway epithelium cells (16HBE and BEAS2B) induces the colony formaion in soft agar and tumor formation in nude mice. Targeting these cells with xCT overexpression by sulfasalazine significantly reduced tumor burden in mice by 50%. Furthermore, the overexpresion of xCT promotes increased glucose consumption, glutamine consumption and lactate production.
Conclusion: Our results demonstrate that xCT is highly expressed in a subset of NSCLCs. The induction of xCT in transformed aiway epithelial cells causes tumor formation in nude mice. The mechanism of malignant transformation involves the Warburg effect. Further investigation into the mechanisms of transformation may help in answering fundamental questions pertaining to how glutamate/cystine exchange contributes to lung cancer development and progression and also in establishing xCT as a potential novel therapeutic target in lung cancer.
Citation Format: Xiangming Ji Ji, Jun Qian, Jamshedur Rahman, Brad Harris, Megan Hoeksema, Heidi Chen, Rosana Eisenberg, Jamey Young. SLC7A11 contributes to the pathogenesis of lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A10.