bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA26: Regulation of metastasis in breast cancer
Authors: Werb Zena 
Published: August 2014

Abstract
Breast cancer patients with metastatic disease have poor prognoses. A key transcription factor, the loss of GATA3 by mutation or loss of expression correlates with a worse prognosis. Indeed, GATA3 is the third most mutated gene in breast cancer progression. In mouse and human breast cancer cells, GATA3 suppresses metastasis by promoting tumor cell differentiation and by altering the tumor microenvironment. Although GATA3 has many direct targets, one major pathway downstream of GATA3 regulating metastasis is through its induction of miR29 expression. miR29b is enriched in luminal breast cancers, which are high in GATA3. miR29b inhibits metastasis directly by targeting a network of pro-metastatic regulators involved in angiogenesis, collagen remodeling and proteolysis. Loss of miR29b, even in GATA3-expressing cells increases metastasis and promotes a mesenchymal phenotype. That inhibiting metastasis by regulating tumor microenvironmental genes through a GATA3-miR29b axis opens up potentially new therapies for breast cancer. (Supported by Grant R01 CA129523).
Citation Format: Zena Werb. Regulation of metastasis in breast cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA26.
Abstract IA28: Haploinsufficiency in cancer
Authors: Davoli Teresa , Solimini Nicole L. , Pavlova Natalya N. , Xu Qikai , Mengwasser Kristen , Sack Laura M. , Liang Anthony C. , Schlabach Michael R. , Luo Ji , Burrows Anna E. , Anselmo Anthony N. , Li Mamie Z. , Elledge Stephen J. 
Published: August 2014

Abstract
Breast cancer is a collection of diseases with distinct clinical behaviors and underlying genetic causes. We have searched genetically for genes that have cancer relevant phenotypes including genes that alter cellular proliferation, cellular transformation, cell survival, cellular senescence, and genes that are essential for the proliferation of cancer cells. We have approached this by the generation of libraries of shRNAs for loss of function experiments and libraries of ORFs for gain of function experiments. We will discuss these technologies and how they can be applied to the functional dissection of genes important for breast cancer. Using these new technologies we have identified new oncogenes and tumor suppressors. We find that tumor cells selectively delete negative growth regulators and suggest that the deletion of clusters of these genes may drive tumorigenesis by haploinsufficiency. These recurrent deletions also avoid deletion of one copy of many essential genes through haploinsufficiency. We put forward the Cancer Gene Island model that postulates that tumors select for hemizygous loss of islands of gene enriched in negative regulators of proliferation and depleted in essential genes to promote tumor cell proliferation through cumulative haploinsufficiency.
Citation Format: Teresa Davoli, Nicole L. Solimini, Natalya N. Pavlova, Qikai Xu, Kristen Mengwasser, Laura M. Sack, Anthony C. Liang, Michael R. Schlabach, Ji Luo, Anna E. Burrows, Anthony N. Anselmo, Mamie Z. Li, Stephen J. Elledge. Haploinsufficiency in cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA28.
Abstract IA7: Translational control of cancer via eIF4E/4E-BPs
Authors: Sonenberg Nahum 
Published: August 2014

Abstract
Control of translation initiation plays an important role in cell growth, proliferation and cancer development and progression. mRNA translation is dysregulated in many cancers via a combination of protein overexpression and defects in the pathways that signal to the translation machinery. In support of the critical function of translational control in cancer is the discovery of mutations in translational components in genetic syndromes associated with cancer susceptibility.
A key regulator of translation initiation is the mRNA 5'-cap-binding protein, eIF4E. eIF4E overexpression engenders transformation of rodent and human cells and causes cancer in mice. eIF4E levels and phosphorylation are elevated in many types of human cancers. Phosphorylation of eIF4E on Ser209 is required for efficient transformation by eIF4E. We generated eIF4E ‘knock-in’ mice in which Ser209 was mutated to alanine. These mice were resistant to prostate cancer induced by PTEN deletion, or cancers induced by other means.
An important downstream component of the PTEN/Akt/mTOR signaling pathway, which is strongly implicated in cancer etiology, is the translation machinery. A well-characterized target of mTOR is 4E-BP1, which binds to eIF4E and inhibits cap-dependent translation. mTOR forms two distinct complexes, mTORC1 and mTORC2. mTORC1 integrates growth factor and nutrient signals to control cell proliferation (increase in cell number) and cell growth (increase in mass). mTORC1 controls these processes by stimulating mRNA translation via phosphorylation of its two major downstream targets: the 4E-binding proteins (4E-BP1, 2 and 3) and the S6 kinases (S6K1 and 2). 4E-BPs impair the assembly of the eIF4F pre-initiation complex by competing with eIF4G for binding to eIF4E, whereas S6Ks phosphorylate a number of targets including ribosomal protein S6 and eIF4B. We showed that the 4E-BPs do not affect cell size, but strongly inhibit cell proliferation, by selectively inhibiting the translation of mRNAs encoding for proliferation-promoting proteins, and proteins involved in cell cycle progression.
The hyperactivation of the mechanistic/mammalian target of rapamycin (mTOR) occurs in the majority of cancers. Therefore, targeted inhibition of mTOR is an attractive anti-cancer strategy. We show that high expression of eIF4E confers increased resistance of cells to the anti-proliferative effects of asTORi. Conversely, depletion of eIF4E levels by RNAi potentiates the anti-neoplastic effects of asTORi in vitro and in vivo. Anti-sense therapy against eIF4E is presently evaluated in clinical trials against cancers. Our data indicate that combining this strategy with targeted mTOR inhibition could have increased therapeutic benefits.
Citation Format: Nahum Sonenberg. Translational control of cancer via eIF4E/4E-BPs. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA7.
Abstract IA8: Novel insights into synthetic lethal interactions in cancer: Common nodes in protein synthesis control and nucleotide metabolism
Authors: Ruggero Davide 
Published: August 2014

Abstract
Our research is centered on understanding the molecular mechanisms by which impairments in accurate control of mRNA translation, cell growth, and overall cellular protein synthesis rates lead to cancer and human disease. We have uncovered that a common denominator of multiple oncogenic pathways (i.e. PI3K-AKT-mTOR, Ras, Myc) is their ability to directly control the core translation machinery of a cell, resulting in intrinsic regulation of the cancer cell gene expression program. Our work delineates how the “cancer translatome” can reprogram gene expression at the post-transcription level, by controlling the translation of specific subsets of mRNAs through unique cis-acting elements, during distinct steps of cancer progression. The immediate impact of these studies has been the design of a new generation of compounds to target the aberrant translation machinery, presently in clinical trials. I will discuss our most recent findings revealing that oncogenic pathways have evolved self-sustaining circuitries that couple two fundamental cellular processes, protein synthesis and metabolism, to sustain the unchecked growth potential of cancer cells. By employing an unbiased metabolomics approach combined with mouse genetics, our findings unveil a critical feed-forward mechanism by which Myc's ability to elevate the protein synthesis capacity of cancer cells directly reprograms nucleotide biosynthesis pathways as a mechanism to sustain tumor growth and survival. I will further discuss how both PI3K-AKT-mTOR and Myc converge on phosphorylation of 4EBP1, a master regulator of protein synthesis control, setting the stage for a unique therapeutic approach to render Myc druggable in the clinic. Together, our findings reveal that targeting either hyperactivation of protein synthesis or nucleotide production represents a novel and unexpected synthetic lethal mechanism for eradicating cancer but not normal cells.
Citation Format: Davide Ruggero. Novel insights into synthetic lethal interactions in cancer: Common nodes in protein synthesis control and nucleotide metabolism. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA8.
Abstract PR01: Genome wide profiling reveals stimulus-specific functions of p53 in human embryonic stem cells
Authors: Jain Abhinav K. , Akdemir Kadir C. , Allton Kendra , Aronow Bruce , Xu Xueping , Cooney Austin J. , Li Wei , Barton Michelle C. 
Published: August 2014

Abstract
p53 is a critical guardian of somatic cells in the face of cellular stress and genomic challenges. Recent work shows that functions of transcription factor p53 go beyond its well-studied roles in tumor suppression. In addition to functions in cell cycle arrest and apoptosis, p53 is a functional barrier to reprogramming adult cells into induced pluripotent (iPS) cells that are phenotypically similar to embryonic stem (ES) cells. How p53 is regulated and functions in stem cells, is poorly understood. Previously we have shown that p53 plays a significant role that depends on its transcriptional activity in early differentiation of human ES cells (hESCs), as induced in vitro by retinoic acid (RA). In order to delineate p53 transcriptional functions during differentiation and how p53 selectively responds to specific signals in hESCs we performed genome wide profiling of p53 chromatin interactions and target gene expression in hESCs in response to early differentiation or DNA damage. The majority of p53 binding sites is unique to each state and defines stimulus-specific p53 response in hESCs. p53 binding regions specific to differentiation significantly overlap with those of core-pluripotency factors OCT4 and NANOG. Differentiation-specific p53 targets are highly expressed, and include many developmental transcription factors, poised by OCT4/NANOG and bivalent histone marks (H3K4me3 and H3K27me3) in pluripotent hESCs. Activation of poised genes during differentiation is associated with elimination of H3K27me3 marks, which is largely dependent on p53. During hESC differentiation, p53 interacts with H3K37me3 specific de-methylases (JMJD3 and UTX) that are enriched at the upstream regions of poised genes resulting in alteration of bivalent histone status and subsequent gene activation. These studies suggest that p53 plays essential roles in regulating epigenetic bivalency in ES cells. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in cell death and cell cycle regulation are conserved in both DNA damage and differentiation. Thus, our findings expand the registry of p53-regulated genes to define p53-mediated opposition to pluripotency during early differentiation, a process highly distinct from stress-induced p53 response in hESCs.
This abstract is also presented as poster A68.
Citation Format: Abhinav K. Jain, Kadir C. Akdemir, Kendra Allton, Bruce Aronow, Xueping Xu, Austin J. Cooney, Wei Li, Michelle C. Barton. Genome wide profiling reveals stimulus-specific functions of p53 in human embryonic stem cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR01.
Abstract A16: Stromal LOX promotes TGFβR2 null breast cancer metastasis
Authors: Pickup Michael W. , Owens Philip , Gorska Agnes , Chytil Anna , Weaver Valerie , Moses Harold 
Published: August 2014

Abstract
To understand how loss of TGF-β signaling in cancer cells promotes tumor progression, we are evaluating modifications to the extracellular matrix in TGF-β type II receptor KO tumors. Tumor cell invasion is a dynamic process which is regulated by many microenvironmental influences such as ECM composition, MMP activity, and exposure of proper integrin binding sites. Crosslinking of collagen fibers increases the overall stiffness of affected tissue providing the mechanical force necessary for tumor cell migration and invasion. Lysyl oxidase is a potent extracellular enzyme that crosslinks collagen and elastin fibers. The study of human breast cancer cell lines shows that highly invasive cells express higher levels of lysyl oxidase and treatment with a lysyl oxidase inhibitor significantly decreases cellular invasion. Recent reports suggest that hypoxia induced metastasis is facilitated by lysyl oxidase crosslinking of the extracellular matrix. TGF-β is another molecule that is known to promote lysyl oxidase expression and will be the focus of our studies.
In this study we utilize transgenic mice which express PyMT under a mammary epithelial specific promoter and have the type II TGF-β receptor conditionally deleted from mammary epithelial cells. Prior to tumor palpation, we see an increase in collagen deposition as well as tissue tensile strength indicating the presence of a higher degree of collagen crosslinking. In PyMT tumors originating from the RII KO mammary glands, increased deposition and maturation of collagen is present in the tumor microenvironment. However, this is not correlated with an increased expression of collagen genes. Subsequent analysis has shown an increased expression and activity of lysyl oxidase present in these TGFβR2KO PyMT tumors. Increased levels of lysyl oxidase are correlated with increased levels of available TGF-β in the RII KO tumors. Upon in vivo inhibition of lysyl oxidase, with beta-aminoproprionitrile, we see a significant decrease in tumor metastasis to the lungs through the inability to escape into the vasculature. Interestingly, these phenotypes are not driven by hypoxia, as shown in previous publications, and instead appear to be driven by TGFβ signaling in the stroma of these tumors. With the source of the TGFβ driving the increase expression of stromal LOX appears to be infiltrating immune cells, MDSCs. This work points to a new paradigm of LOX induction in tumors and presents a new therapeutic target group for LOX inhibition outside of patients presenting with hypoxic tumors.
Citation Format: Michael W. Pickup, Philip Owens, Agnes Gorska, Anna Chytil, Valerie Weaver, Harold Moses. Stromal LOX promotes TGFβR2 null breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A16.
Abstract A23: Cell autonomous and nonautonomous activities of heat shock factor 1 support tumor initiation, progression, and metastasis
Authors: Scherz-Shouval Ruth , Santagata Sandro , Koeva Martina , Whitesell Luke , Lindquist Susan 
Published: August 2014

Abstract
The heat-shock response is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding through the induction of heat shock proteins (HSP), but to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this response is regulated primarily by the Heat Shock Factor 1 (HSF1) transcription factor. We have previously shown that HSF1 plays a fundamental role in tumorigenesis, by promoting the survival and malignance of tumor cells, both in tissue culture and in mouse models of cancer [1].
Recently we demonstrated that HSF1 exerts its role by activating a unique transcriptional program in the cancer cells, that is distinct from the one activated during heat shock [2]. In breast cancer and several other types of carcinoma, we found that high HSF1 protein levels and activation of the HSF1-dependent transcriptional program are associated with poor clinical outcome [3]. Here we show that HSF1 is activated not only in the tumor cells, but also in the stromal cells infiltrating the tumor. Examining human patient samples, we find immunohistochemical evidence for activation of HSF1 in the stroma. Using mouse xenograft models and in vitro co-culture we show that HSF1 in the stroma supports tumor cell growth. Finally, expression profiling and analysis of the DNA binding pattern of HSF1 in tumors and in cell culture indicates that stromal HSF1 supports tumorigenesis by activating a unique, stroma-specific transcriptional program. Taken together, our data suggests that HSF1 acts in the cancer cells and in the stroma to activate distinct, yet complimentary transcriptional programs that will facilitate tumor initiation, progression and metastasis.
References
1. Dai, C., et al., Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell, 2007. 130(6): p. 1005-18.
2. Mendillo, M.L., et al., HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell, 2012. 150(3): p. 549-62.
3. Santagata, S., et al., High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A, 2011. 108(45): p. 18378-83.
Citation Format: Ruth Scherz-Shouval, Sandro Santagata, Martina Koeva, Luke Whitesell, Susan Lindquist. Cell autonomous and nonautonomous activities of heat shock factor 1 support tumor initiation, progression, and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A23.
Abstract A28: Role of PDGF signaling during the progression of breast ductal carcinoma in situ to invasive carcinoma
Authors: Strell Carina , Paulsson Janna , Wärnberg Fredrik , Johansson Hemming , Jirström Karin , Hall Per , Östman Arne 
Published: August 2014

Abstract
Breast cancer is one of the most common cancer diseases; in Sweden over 7000 women are diagnosed yearly and 1500 die from the disease. About 20 % of newly diagnosed breast cancers are ductal carcinoma in situ (DCIS), an early stage of breast cancer. The majority of DCIS will never become malignant but 15-20 % will proceed to invasive carcinoma and/or metastasize. Predicative markers for invasiveness are highly needed to understand which tumors will recur and to prevent over treatment.
Tumor characteristics are determined by interactions between malignant cells and the microenvironment. Cancer associated fibroblasts (CAFs) are a major component of the tumor microenvironment and one important regulator of their phenotype are the PDGFs, which signal through the PDGFα and β receptors (PDGFRs). Our previous studies in invasive breast carcinoma have shown that high stromal PDGFβR expression is associated with shorter survival, particularly in pre-menopausal women.
The aim of this study is to investigate the potential prognostic significance of stromal PDGFRs in the transition of breast DCIS to invasive carcinoma.
We found that both PDGFRs are highly expressed in normal breast stroma, whereas DCIS displays loss of periepithelial stromal PDGFαR. In contrast, patients with a high stromal PDGFβR expression in the DCIS lesion, showed a trend for a higher risk of local recurrence or general disease.
These previously un-recognized potentially differential effects of stromal PDGFαR and PDGFβR signaling in breast cancer progression is presently being further explored in animal studies and in vitro experiments.
Citation Format: Carina Strell, Janna Paulsson, Fredrik Wärnberg, Hemming Johansson, Karin Jirström, Per Hall, Arne Östman. Role of PDGF signaling during the progression of breast ductal carcinoma in situ to invasive carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A28.
Abstract A3: Collagen hydroxylases are essential for breast cancer metastasis
Authors: Gilkes Daniele M. , Chaturvedi Pallavi , Wong Carmen , Bajpai Saumendra , Wei Hong , Hubbi Maimon , Wirtz Denis , Semenza Gregg 
Published: August 2014

Abstract
Metastasis is the leading cause of death among patients who have breast cancer. Understanding the role of the extracellular matrix in the metastatic process may lead to the development of improved therapies to treat cancer patients. Intratumoral hypoxia, found in the majority of breast cancers, is associated with an increased risk of metastasis and mortality. Here we demonstrate that hypoxia-inducible factor 1 activates the transcription of genes encoding collagen prolyl hydroxylases that are critical for collagen deposition by breast cancer cells. We identify that expression of collagen prolyl hydroxylases promotes cancer cell alignment along collagen fibers resulting in enhanced cancer cell invasion and metastasis to lymph nodes and lungs. We establish the prognostic significance of collagen hydroxylase expression in human breast cancer biopsies and evaluate the novel use of ethyl 3,4-dihydroxybenzoate, a hydroxylase inhibitor, which decreases tumor fibrosis and metastasis in a mouse model of breast cancer.
Citation Format: Daniele M. Gilkes, Pallavi Chaturvedi, Carmen Wong, Saumendra Bajpai, Hong Wei, Maimon Hubbi, Denis Wirtz, Gregg Semenza. Collagen hydroxylases are essential for breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A3.