bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4001: Lin28/miR-let-7c axis controls the growth and tumorigenicity of prostate cancer cells
Authors: Nadiminty Nagalakshmi , Tummala Ramakumar , Chun Jae Yeon , Lou Wei , Shi XuBao , deVere White Ralph , Gao Allen C. 
Published: June 2012

Abstract
Introduction: MicroRNAs (miRNA) are small ∼22 nt non-coding RNAs that regulate gene expression by binding to and inducing degradation of target mRNAs. Deregulated expression of several miRNAs has been found in prostate cancer cells. Let-7 is an evolutionarily conserved family of miRNAs that have been shown to regulate expression of several oncogenes like HMGA2, RAS and Myc. Expression of members of the let-7 family has been shown to be downregulated in many human cancers including lung, breast, ovarian and prostate. In this study, we examined the relative expression levels of let-7c and its master regulator, Lin28 in prostate cancer cells and clinical specimens. We also examined the role of the let-7/Lin28 axis in controlling proliferation in prostate cancer cells.
Methods: Expression levels of Let-7c and Lin28 in prostate cancer cells and clinical specimens were measured by real-time qRT-PCR, Northern and Western blotting. Prostate cancer cell lines with stable expression of let-7c or Lin28 were generated and their growth characteristics, clonogenic ability and colony forming abilities in soft agar were examined. Expression of let-7c was downregulated in LNCaP cells using antisense oligonucleotides and effects on growth were examined. Lentiviruses containing let-7c were injected into tumors generated by implantation of prostate cancer cells in nude mice and tumor volumes were measured.
Results: Expression levels of let-7c were found to be downregulated in castration-resistant prostate cancer cells and clinical specimens. These levels were found to be inversely correlated to expression levels of Lin28. Overexpression of let-7c reduced prostate cancer cell growth, clonogenic ability and ability to form colonies in soft agar, while downregulation of let-7c resulted in increased cell growth. Conversely, overexpression of Lin28 enhanced prostate cancer cell growth and clonogenic ability. In addition, intratumoral injection of lentiviruses containing let-7c reduced tumor volumes significantly in vivo in nude mice compared to control viruses.
Conclusions: Levels of miR-let-7c are reduced in CRPC compared to androgen-dependent prostate cancer. Levels of Lin28, which regulates processing of let-7c into its mature form, are elevated in CRPC. Overexpression of let-7c reduces prostate cancer cell growth and tumorigenic ability. These results suggest that miR-let-7c is a tumor suppressor and may be developed as a therapeutic agent against CRPC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4001. doi:10.1158/1538-7445.AM2011-4001
Abstract 4007: Defining the role of ERG-mediated repression of HPGD in prostate tumorigenesis
Authors: Ahmed Mohamed , Tan Shyh-Han , Sun Chen , Shaheduzzaman Syed , Hu Ying , Petrovics Gyorgy , Chen Yongmei , Li Hua , Sesterhenn Isabell , Sreenath Taduru , McLeod David G. , Dobi Albert , Srivastava Shiv 
Published: June 2012

Abstract
Activation of the ETS Related Gene (ERG) was originally identified in subsets of Ewing sarcomas, myeloid leukemias and, recently, in the majority of prostate cancers (CaP). Emerging studies in experimental models underscore functions of ERG in prostate tumorigenesis. However, biological functions of ERG in CaP remains to be better understood. Evaluation of ERG downstream targets identified 15-hydroxyprostaglandin dehydrogenase gene (HPGD) in response to ERG knockdown. Several recent studies have indicated that HPGD, the main catabolizing enzyme of prostaglandins and lipoxins and a tumor suppressor, is down-regulated in a majority of lung, colon, breast, and bladder cancers. However, the regulation of HPGD within the biological context of ERG expressing prostate tumors remains to be defined. The objective of this study was to evaluate the effects of ERG on the prostaglandin signaling pathway in prostate cancer.
Correlation between HPGD and ERG expression was evaluated at the mRNA and protein levels in prostate cancer specimens and cell lines by Western blot, QRT-PCR, and immunofluorescence assays. Small interference RNA against human ERG and HPGD were used to knock-down their respective expressions. Functional consequences of ERG and HPGD knockdown in VCaP cells harboring TMPRSS2-ERG fusions were assessed by ChIP and BrdU cell proliferation assays.
The experiments showed that loss of ERG expression leads to a robust overexpression of HPGD in prostate cancer cells. Furthermore, we observed altered PGE2 production, decreased expression of prostaglandin E2 receptor 4 (EP4), and inhibition of prostaglandin E2 induced cell growth. Chromatin immunoprecipitation experiments revealed direct binding of ERG protein to the HPGD core promoter. Comparison of HPGD expression in TMPRSS2-ERG positive and negative prostate tumors indicated a trend towards decreased HPGD expression.
In conclusion ERG activation, as a consequence of TMPRSS2-ERG fusions, may influence the components of the prostaglandin signaling pathway in prostate tumorigenesis disrupting the tumor suppressor functions of HPGD. These findings suggests for a new biological role of ERG in CaP that may be further evaluated as a target for prevention, as well as early therapeutic intervention in CaP.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4007. doi:10.1158/1538-7445.AM2011-4007
Abstract 401: Inducible nitric oxide synthase suppresses the expression of CXCL10 and hence leads to the poor outcome of Stage III malignant melanoma
Authors: Tanese Keiji , Ekmekcioglu Suhendan , Grimm Elizabeth 
Published: June 2012

Abstract
Melanoma is the deadliest form of skin cancer and exhibits extremely aggressive growth characteristics. Accumulating evidence suggests that melanoma is heterogeneous in response to therapies as well as etiology, survival with advanced disease, and tumor mutational status. Our previous studies showed that the expression of inducible nitric-oxide synthase (iNOS) in melanoma tumor cells strongly correlate with poor patient survival. We are hypothesizing that iNOS is a key molecule in melanoma signature comprising an inflammatory microenviroment of poor outcome. To gain further insight into the nature of the melanoma inflammatory microenvironment, PCR array related to inflammatory and autoimmunity gene was done on a series of Stage 3 melanoma lymph node metastases samples to compare the gene expression level directly between iNOS-positive and -negative tumor samples. As a result, we found the significant correlation between iNOS expression and suppression of CXC Chemokine ligand 10 (CXCL10) in mRNA and protein levels. In the set of 16 cases of Stage3 melanoma samples, high CXCL10 expressing group showed the favorable prognosis compared to low CXCL10 expressing group. In the further in vitro analysis, we found that nitric oxide (NO) provided by S-nitroso-N-acetyl-l,l-penicillamine suppresses the expression of CXCL10 in iNOS negative and CXCL10 positive melanoma cell. Quenching the NO with NO scavenger, 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide in iNOS positive and CXCL10 negative cell lines induces the expression of CXCL10. CXCL10 is reported to play the role in the recruitment of cytotoxic immune cells such as CD8+ T cells, and NK cells into the tumor microenvironment. CXCL10 also has a function of antagonizing the activities of angiogenic factors such as bFGF and IL-8 and it is considered as an anti-tumorigenic protein. Our study suggests that production of NO by iNOS inhibits the expression of CXCL10 in melanoma and comprises the pro-tumorigenic tumor microenvironment. Inhibition of NO may have a possibility to render the tumor microenvironment to anti-tumorigenic status. Therefore, iNOS will be a good target in the treatment of melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 401. doi:10.1158/1538-7445.AM2011-401
Abstract 4011: Evidence supporting a role of c-Myb in pancreatic cancer
Authors: Singh Seema , Srivastava Sanjeev K. , Bhardwaj Arun , Owen Laurie B. , Grizzle William E. , Singh Ajay P. 
Published: June 2012

Abstract
The clinical outcome from pancreatic cancer has not improved over the years. This is, in part, due to not well understood disease mechanisms and consequently there is little progress made in developing intervention therapy. Many genetic alterations have been characterized in pancreatic cancer, of which some have been shown to be functionally relevant. In an earlier study, c-Myb was identified as a candidate oncogene in pancreatic cancer with gene amplification in a subset and overexpression in majority of pancreatic cancer tissues and cell lines. The role of c-Myb in pancreatic cancer, however, has not been defined so far. c-Myb is a cellular progenitor of v-Myb oncogenes, which encodes for a transcription factor and confers its oncogenic activity by regulating the expression of several target genes. To examine the functional role of c-Myb in pancreatic cancer, we silenced its expression in two pancreatic cancer cell lines (Panc1 and MiaPaCa) by stable transfection of a c-Myb-targeted short-hairpin RNA (shRNA)-expression plasmid. Silencing of c-Myb expression resulted in diminished growth and clonogenicity of pancreatic cancer cells. c-Myb knockdown pancreatic cancer cells were arrested at G1/S boundary of cell cycle, and exhibited enhanced apoptosis. Furthermore, we observed decreased migration and invasion in c-Myb silenced pancreatic cancer cells as compared to the control cells. Immunoblot analysis demonstrated gain of epithelial- and loss of mesenchymal- markers in c-Myb knockdown pancreatic cancer cells, thus indicating a reversal of epithelial to mesenchymal transition (EMT). We also observed noticeable changes in cell morphology and actin-organization upon silencing of c-Myb expression that were consistent with loss of mesenchymal features. Together, these findings provide first experimental evidence for a functional role of c-Myb in pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4011. doi:10.1158/1538-7445.AM2011-4011
Abstract 4013: Transcriptional regulation of EGR1 by EGF and the ERK signaling pathway in prostate cancer
Authors: Gregg Jennifer L. , Fraizer Gail C. 
Published: June 2012

Abstract
The early growth response gene 1, EGR1, is an important transcriptional regulator and acts as the convergent point between a variety of extracellular stimuli and activation of target genes resulting in diverse responses such as cell growth, proliferation, and apoptosis. Unlike other tumor types, in prostate tumor tissues EGR1 expression is elevated relative to normal tissues. However, the mechanism(s) of regulation of EGR1 in prostate tumor cells are unknown. As EGR1 expression and epidermal growth factor (EGF) signaling are frequently upregulated in prostate tumors, we tested the hypothesis that EGF induces EGR1 expression in prostate cancer cells. Using real-time PCR to quantify EGR1 transcripts, EGF induced EGR1 expression levels in a dose and time-dependent manner; and kinase inhibitors, PD98059 and wortmannin, abrogated the EGF-mediated EGR1 response. Analysis of the EGR1 promoter using reporter constructs identified an EGF-responsive region in the proximal promoter containing three potential serum response element (SRE) sites. In vivo chromatin immunoprecipitation assays demonstrated that EGF enhanced Elk-1 binding at the SRE sites of the EGR1 promoter in PC3 cells, and Elk-1 also bound in the absence of stimulus. Overexpression of Elk-1 enhanced activation of the EGF-responsive region indicating that Elk-1 is sufficient to activate EGR1 in PC3 cells. Similarly, a dominant-negative Elk-1 suppressed EGR1 promoter activity indicating that Elk-1 is necessary for EGF-induced EGR1 transcription in both PC3 and LNCaP cells. Taken together, these results demonstrate that EGR1 expression in prostate cancer cells is mediated through an EGF-ERK-Elk-1 signaling cascade. Since elevated EGF and EGF receptor are associated with prostate cancer progression, these results may explain elevated EGR1 in high-grade prostate tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4013. doi:10.1158/1538-7445.AM2011-4013
Abstract 4018: The role of FLI1 in breast cancer development and progression
Authors: Scheiber Melissa Nicole , Watson Patricia M. , Findlay Victoria J. , Rumboldt Tihana , Watson Dennis K. 
Published: June 2012

Abstract
Breast cancer is the second most common cancer-related death among women in the US. The majority of the breast cancer-related deaths are due to tumor progression. A multitude of changes in gene expression are required for the cancer cell to acquire the ability to invade and migrate. The transcriptional activation or repression of these cancer-associated genes is not clearly understood, however many ETS family members have been considered good candidates. Friend leukemia virus integration 1 (FLI1) is an ETS protein that is aberrantly expressed in retrovirus-induced hematological tumors, and is found to be rearranged in Ewing's sarcoma and related primitive neuroectodermal tumors characterized by a t(11;22)(q24;q12) translocation. Limited attention has been directed towards elucidating the potential role of FLI1 in epithelial-derived cancers, including breast cancer. Our preliminary immunohistochemical analyses show that FLI1 protein is decreased in human invasive breast tumors compared to normal breast tissue. A decrease of FLI1 mRNA and protein was also demonstrated in breast cell cancer cell lines through Real Time RT-PCR and western blot, respectively. We used adenovirus to examine the effects of FLI1 expression in two invasive breast cancer cell lines (MDA-MB-231 and MDA-MB-157). Re-expression of FLI1 in both MDA-MB-231 and MDA-MB-157 inhibited cell growth, mainly due to a decrease in cellular proliferation. FLI1 expression also inhibited the motility and invasiveness of breast cancer cell lines, determined by the use of Transwell inserts coated with fibronectin or Matrigel, respectively. We hypothesize that the loss of FLI1 is a critical step for breast cancer progression. Loss-of-function studies using shRNA are being performed to complement the above gain-of-function studies. Future studies will investigate potential downstream targets of FLI1. Inhibiting the reduction of FLI1 or regulating its downstream targets may be to be unique targets of breast cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4018. doi:10.1158/1538-7445.AM2011-4018
Abstract 4023: ARID1A is a candidate tumor suppressor gene in breast cancer
Authors: Chabot Catherine , Mamo Aline , Cavallone Luca , Tuzmen Sukru , Hassan Saima , Edgren Henrik , Ferrario Cristiano , Aleynikova Olga , Przybytkowska Ewa , Malcolm Kristin , Kallioniemi Olli , Tonin Patricia , Mousses Spyro , Basik Mark 
Published: June 2012

Abstract
Tumor suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. Typically but not always, tumors neutralize both alleles of TSGs by deleting one copy and mutating the other. One molecular strategy to discover potential tumor suppressor gene candidates involves the “re-expression” of RNA transcripts containing nonsense mutations by inhibition of the nonsense-mediated RNA decay (NMD) process. Combining NMD inhibition with array CGH has lead to the genome-wide identification of genes with biallelic inactivation (involving nonsense mutations on one allele and loss of the second allele) in prostate cancer cell lines and identified EphB2 as a novel candidate TSG in prostate cancer. Using such a strategy in 5 breast cancer cell lines, we identified ARID1A as a NMD target in the T47D breast cancer cell line. ARID1A encodes a human homologue of yeast SWI1, which contains a DNA-binding motif (AT-rich interactive domain, ARID) and is an integral member of the hSWI/SNF complex, an ATP-dependent chromatin-remodeling multiple-subunit enzyme. Mutations in the ARID1A gene were recently reported to be present in 50% of clear cell tumors of the ovary. We found the ARID1A gene contains a nonsense mutation in exon 9, which introduces a premature stop codon, changing Q944 to a stop codon in the T47D breast cancer cell line. Although we did not find any somatic mutations in breast tumors, we show that low ARID1A RNA expression or low ARID1A nuclear protein expression is associated with more aggressive breast cancer phenotypes in 2 independent cohorts of over 200 breast cancers each. We also found that low or absent ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the breast cancer cell line in which it is mutated results in significant inhibition of colony formation in soft agar. These results suggest that the ARID1A gene may be a candidate tumor suppressor gene in breast cancer, and that it warrants further investigation as potential diagnostic and therapeutic marker in breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4023. doi:10.1158/1538-7445.AM2011-4023
Abstract 4024: ING4 tumor suppressor binds to estrogen receptor-complex and modulates estrogen-dependent cell growth and gene expression in breast cancer
Authors: Dempsey Katherine J. , Whitsett Timothy G. , Kim Suwon 
Published: June 2012

Abstract
The tumor suppressor ING4 (Inhibitor of Growth family member 4) has been shown to play a role in diverse cancer-related cellular processes, including gene regulation, apoptosis, cell migration, contact inhibition, and angiogenesis. Deletion or reduced expression of ING4 has been shown in a number of human malignancies, including breast cancer. We found ING4 to be deleted in 15% of estrogen receptor-positive (ER+) breast cancers, implicating a role for ING4 as a tumor suppressor in estrogen-driven breast cancer. In addition, we showed that over-expression of ING4 abrogated, whereas ING4 knock-down enhanced, estrogen-dependent cell growth of MCF7 ER+ breast cancer cells, indicating a suppressive function of ING4 in estrogen-dependent cell growth. The molecular mechanisms of ING4 in ER+ breast cancers have not yet been elucidated.
Using a bacterial two-hybrid screen, we identified CCAR1 (Cell-Cycle and Apoptosis Regulatory Protein 1) as an ING4 binding protein. Subsequently, we validated interactions between ING4 and CCAR1 in 293T and MCF7 cells using co-immunoprecipitation assays. CCAR1 had previously been shown to be a co-activator of the estrogen receptor (ER) complex that is required for estrogen-dependent cell growth and gene transcription in ER+ breast cancer cells (Kim JH, Yang CK, Heo K, Roeder RG, An W, and Stallcup MR, 2008). Taken together, these results suggested that ING4 may interact with the ER-complex and implicated a role for ING4 in the ER-mediated cellular processes. Here we show that ING4 co-immunoprecipitates with estrogen receptor-alpha (ERα) and the co-activator AIB1 in MCF7 and T47D ER+ breast cancer cells, demonstrating ER:ING4 interactions in cells. Treatment with 17β-estradiol (E2) reduced ING4:ER interactions. These results suggested that ING4 may not be a co-factor in the estrogen-bound active ER-complex, supporting our hypothesis that ING4 plays a role in the modulation of the ER-complex. Strikingly, tamoxifen treatment greatly enhanced ING4 association with ERα, suggesting that tamoxifen stabilizes ER:ING4 interactions and/or ING4 has a greater binding affinity to the tamoxifen-bound ER-complex. It is possible that ING4 plays a role in the recruitment of co-repressors to the tamoxifen-bound ER-complex. These results implicate a role for ING4 in tamoxifen response. We conclude that ING4 may function as a tumor suppressor in ER+ breast cancers by binding to the ER-complex and modulating estrogen-dependent cellular processes including cell proliferation and gene transcription.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4024. doi:10.1158/1538-7445.AM2011-4024
Abstract 4037: Loss of Par3 induces an epithelial to metastatic-epithelial transition during ErbB2 induced mammary tumor progression
Authors: Xue Bin , Krishnamurthy Kannan , Muthuswamy Senthil K. 
Published: June 2012

Abstract
The Partitioning defective (Par) proteins are part of an evolutionarily conserved complex that is known to regulate asymmetric cell division, cell junction biogenesis and epithelial morphogenesis, but the role they play in cancer is not well understood. Here we demonstrate that loss of Partitioning defective 3 (Par3) cooperates with activation of the receptor tyrosine kinase ErbB2 to induce migration and invasion of normal and tumor-derived human mammary epithelial cells. Surprisingly, the acquisition of invasive ability was not associated with an overt mesenchymal transition as determined by a lack of expression of mesenchymal markers and retention of an epithelial morphology. We demonstrate that loss of Par3 induces aberrant activation of the small GTP binding protein Rac, loss of cortical actin and a decrease in cell-cell adhesion. Par3 is known to interact with and inhibit the Rac exchange factor Tiam1, consistently, ectopic expression of Tiam1 phenocopied Par3 loss and was sufficient to cooperate with ErbB2 to induce invasion and a decrease in intercellular adhesion. Inhibition of Tiam1-induced Rac activation restores cortical actin network and cell-cell junctions and blocks ErbB2-induced migration and invasion. Expression of Par3 was downregulated in both human breast cancer and in the metastasis resulting from ErbB2-expressing primary mouse mammary tumors. Forced downregulation of Par3 in ErbB2-tumor-derived primary epithelial cells promoted metastasis in vivo demonstrating that loss of Par3 is sufficient to initiate metastatic progression of ErbB2-induced mammary tumors. Thus, loss of Par3 induces metastatic properties to epithelial cells while expression of Par3 is required to maintain a non-metastatic epithelial state of tumor cells. Our observations on metastatic epithelia identify a novel mechanism by which tumor cells metastasize while retaining epithelial characteristics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4037. doi:10.1158/1538-7445.AM2011-4037