bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1187: The role of PI3K as a biomarker
Authors: Amatulli Michael , Brennan Laura A. , Deevi Dhanvanthri S. , Prewett Marie , Tonra James R. , Paz Keren 
Published: February 2011

Abstract
The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been implicated in tumorigenesis. Evidence over the past years suggests a pivotal role for the catalytic subunit, PIK3CA, in human cancers. Receptor tyrosine kinases (RTKs) on the cell surface are key regulators of PI3K activity, and RTK antagonists have demonstrated significant anticancer effects in animal models and in patients. However, among tumor harboring activating mutations of PIK3CA, the therapeutic value of RTK antagonists may be compromised. The mutation status of PIK3CA may, therefore, serve as a potential biomarker for both prognosis and response to RTK inhibitors.
Somatic mutations of the pik3ca gene occur primarily in three hot spots, E542K, E545K (exon 9) and H1047R (exon 20). These mutations are detected in a broad spectrum of cancer indications including breast, colorectal and lung. This study was designed to explore the nature of PIK3CA mutations among numerous human cancer cell lines, utilizing mostly cells with the capacity to form tumors in mice. Primers corresponding to exon 9 and 20 of human pik3ca gene were designed. Genomic DNA was harvested from over 200 lines, derived from different human cancer indications. The pik3ca locus was sequenced and its WT or mutation status was determined.
Of these cells, 8% presented mutations equally distributed between exon 9 and 20. The frequency of PIK3CA mutations was particularly high among colon cancer lines, with fewer incidences among lung, breast and ovarian cancer lines. Interestingly, 50% of the PIK3CA mutated lines presented a concurrent mutation of either KRAS or BRAF. The capacity of PIK3CA mutation-bearing cell lines to respond to RTK blockers was then evaluated, and the mechanism contributing to such phenomenon was further discussed.
These results stress PI3K diagnosis value and its potential role as a valid biomarker for patient susceptibility.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1187.
Abstract 1191: Flotillin-2 overexpression is associated with an invasive urothelial cell carcinoma phenotype
Authors: Veerakumarasivam Abhimanyu , Saeb-Parsy Kasra , Scott Helen E. , Neal David E. , Kelly John D. 
Published: February 2011

Abstract
Invasive urothelial cell carcinoma (UCC) is associated with poor clinical outcome and is characterized by a genotype that is distinct from superficial disease. Exploiting a multi-component mining strategy on a set of high-throughput genome-wide experimental data, we probed for genes associated with an invasive phenotype. Fresh frozen UCC tissues were profiled using global expression microarrays and array-based comparative genomic hybridization (aCGH). Differentially expressed genes were functionally annotated by gene ontology and compared to available SAGE libraries and expression array datasets. We identified overexpression of a lipid raft associated protein, Flotillin 2 (FLOT2) in invasive UCC. The FLOT2 locus (17q11-q12) was associated with copy number gains in 15% of the tumors. We further characterized Flot2 protein expression in an independent tissue microarray series by immunohistochemistry. Flot2 protein expression increased with clinical risk. Interestingly, carcinoma in situ (CIS) tumors demonstrated highest level of expression. In vitro, FLOT2 expression increased with the degree of invasiveness of the UCC cell lines. Knockdown of FLOT2 lead to a significant reduction in the invasive phenotype; whilst overexpression of wild-type FLOT2 enhanced invasion in non-invasive cells. The precise mode of action of Flot2 remains to be elucidated but it is predicted to play an important role in transmembrane signal transduction, cell adhesion and endocytosis. FLOT2 overexpression has also been shown to enhance the spreading of cells, formation of filopodia as well as melanoma progression and metastasis. Thus, the functional targeting experiments and gene-dosage dependent FLOT2 overexpression in invasive UCC confirm a link between FLOT2 and pro-invasive cancer phenotype.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1191.
Abstract 1193: Prospective validation of multiple biomarkers for improved clinical decision-making in patients with urothelial carcinoma of the bladder
Authors: Lotan Yair , Youssef Ramy , Shariat Shahrokh F. , Alhalbi Feras , Ashfaq Raheela , Sagalowsky Arthur I. 
Published: February 2011

Abstract
Objectives: To prospectively assess the predictive value of a panel of biomarkers (cyclin E1, p53, p21, p27 and pRB/Ki-67) for staging of patients with urothelial carcinoma of the bladder (UCB).
Methods: 174 consecutive patients treated with transurethral resection (TUR) and/or radical cystectomy (RC) for UCB were prospectively included in the study starting in January 2007. Standardized, automated immunohistochemical staining and scoring was performed. A prognostic score (PS; ≤2 altered biomarkers=Favorable; &gt;2 altered biomarkers=Unfavorable) was defined and correlated with clinical and pathological data.
Results: The study comprised of 102 RC patients and 72 TURBT cases. Unfavorable PS were noted in 36.3 % of RC cases and 16.6 % of TURBT cases matching the more advanced pathological stages of RC patients. In RC group; an unfavorable PS was significantly associated with advanced tumor stage (p=0.02), the presence of LVI (p=0.017), recurrence (p=0.02) and survival (p=0.048). In the subgroup of patients who had biomarker evaluation at TUR and then underwent RC (n=32), 75 % and 50% of the cases with unfavorable PS showed upstaging and LN involvement at RC versus 25 % and 12.5 % in cases with favorable PS. Unfavorable PS at TUR was associated with the presence of LVI (p=0.001) and LN metastasis (p=0.026). Conclusions: The preliminary analysis of our ongoing prospective trial strongly suggests that a panel of five biomarkers improves the identification of patients at risk of upstaging at RC. An unfavorable PS may identify patients who are most likely to benefit from neo-adjuvant and adjuvant chemotherapy combined with RC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1193.
Abstract 120: Cellular import of the inhibitor of apoptosis (IAP) protein survivin
Authors: Khan Salma , Slater Jessica M. , Neidigh Jonathan W. , Wall Nathan R. 
Published: February 2011

Abstract
The inhibitor of apoptosis (IAP) protein survivin is found overexpressed in virtually all human cancers and has been shown to correlate with poor prognosis. Recent work performed by our laboratory and that of others has demonstrated that survivin, when found or expressed extracellularly, is associated with a more aggressive disease form. In a variety of cancer cell lines grown in conditioned medium, rich with a flag/HA-tagged form of survivin, intracellular accumulation was readily detected. We found that survivin was internalized constitutively at a rate that was not affected by chelation of the conditioned medium in HeLa S cervical cancer cells. Instead, survivin internalization was modestly affected by lipid membrane stasis, induced by cooling the cells and the conditioned medium prior to and during incubation leading us to investigate if survivin's intracellular accumulation was dependent upon clathrin-coated pit-dependent endocytosis. Using dual-affinity protein purification and mass-spectrometry, survivin was found associating directly with clathrin, TNFR1, and the transferrin receptor (TfR), indicating that the process of survivin uptake may be through endocytosis. In addition, short-inhibitory RNA (siRNA) knockdown of TNFR1 and TfR as well as antibody blocking of these receptors significantly reduced survivin's intracellular accumulation. Further characterization of this novel survivin pool and its intracellular accumulation may reveal new strategies for the downregulation of survivin in cancer and ultimately better treatment strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 120.
Abstract 1202: MDM2 and its interaction with MYCN in neuroblastoma survival
Authors: He Jing , Gu Lubing , Li Jiansha , Zhang Hailong , Zhou Muxiang 
Published: February 2011

Abstract
The multifunctional oncoprotein MDM2 plays both p53-dependent and p53-independent roles in cancer initiation, progression and the development of resistance to therapy. Using a siRNA strategy to silence MDM2, which is highly expressed in neuroblastoma, we discovered that MDM2 regulates tumor cell growth and survival through distinct mechanisms in MYCN-amplified and non-MYCN-amplified neuroblastomas. MDM2 inhibition in a MDM2-overexpressing/non-MYCN-amplifying neuroblastoma cell line, SH-EP1, resulted in p53 activation, growth inhibition and apoptosis. In contrast, MDM2 inhibition in the MDM2-overexpressing/MYCN-amplifying neuroblastoma cell lines NB-1691 and IMR32 did not activate p53, despite expression of wild-type p53 in these lines. However, the siRNA silencing of MDM2 in NB-1691 and IMR32 cells did lead to complete inhibition of cell proliferation. In examining MYCN expression in these MYCN-amplified cells, we found that inhibition of MDM2 significantly downregulated MYCN expression at both the mRNA and protein levels. In a p53-null/MYCN-amplifying neuroblastoma cell line, LA1-55N, inhibition of MDM2 also decreased MYCN expression, inhibiting cell growth and apoptosis. These results suggest that MDM2 plays a p53-independent role in MYCN-amplified neuroblastomas. A critical factor for disease progression, we believe deregulation of MYCN expression may contribute significantly to the oncogenic properties of MDM2 in neuroblastoma.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1202.
Abstract 1205: Frequent detection of MDMX isoforms in human ovarian carcinomas
Authors: Loebel Claudia , Wolf Anja , Richter Julia , Thomssen Christoph , Hauptmann Steffen , Bartel Frank 
Published: February 2011

Abstract
The p53 tumor suppressor pathway is inactivated in many human tumors either by p53 mutations or through overexpression of negative regulators, such as MDM2 and MDMX. In analogy to MDM2, besides the full-length mRNA several transcript variants, alternatively, as well as, aberrantly spliced transcripts of MDMX have been identified in different tumor cell lines. However, so far there are no studies regarding the expression of MDMX transcript variants in ovarian cancer tissue samples. We therefore screened 34 snap frozen ovarian tumor samples, using a high-temperature First-Strand cDNA synthesis kit to avoid reverse transcriptase artefacts. We identified in addition to MDMX-S numerous new MDMX transcripts in 16 of the 34 tumor samples that were either spliced at genuine exon/intron boundaries or at cryptic splice sites within exons. Furthermore, we could detect the transcript variants MDMX-A and MDMX-XALT2 firstly in ovarian cancer tissue. The MDMX splice variants can be classified into two groups: some isoforms have only retained the p53 binding domain, such as MDMX-S; in contrast, other splice forms consist of an intact C-terminus including the RING-finger domain, such as MDMX-XALT2. In addition, we have analyzed the expression of MDMX splice forms in ovarian cancer cell lines after treatment with chemotherapeutic agent. We observed a significant increase of the MDMX-S splice form while the expression levels of full-length MDMX decreased. This suggests that MDMX splice forms may play a role in mediating chemoresistance by attenuating the p53-pathway. In ongoing studies, we are investigating the role of frequently detected MDMX splice forms regarding their impact on chemoresistance in ovarian cancer in more detail.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1205.
Abstract 1209: Par-4 as therapy for colon cancer
Authors: Irby Rosalyn B. , Kline Christina L. , Sharma Arun K. 
Published: February 2011

Abstract
Par-4 (Prostate apoptosis response-4) is a tumor suppressor that induces apoptosis in tumor cells in response to apoptotic stimuli. It has been reported to be reduced in a number of human cancers. We examined the expression levels of Par-4 in human colon cancers and explored the possibility of using Par-4 as a treatment for colon cancer. We found that expression of Par-4 is reduced in human colon cancers 2.65-fold compared to paired normal colon. To assess the role of Par-4 in colon cancer growth, the human colon cancer cell line, HT29, with low native Par-4 expression, was transfected to overexpress Par-4. It has been shown that apoptosis was higher in the transfected cells than in the mock transfected cells. It was also shown that tumors growing in nude mice were smaller when the cells were transfected to overexpress Par-4. Importantly for therapeutic considerations, it has been reported that Par-4 expressing cells can have a bystander effect on tumor cells that are not transfected, also inducing apoptosis in the untransfected cells. We hypothesized that HT29 colon cancer cells producing Par-4 in vivo would secrete Par-4 into the animal system and result in lower tumor volume of tumors created with wild type cells growing distally.
Methods: To show proof of concept, nude mice were injected subcutaneously with wild type HT29 cells. Half of the mice were also injected with HT29 cells overexpressing Par-4 in the opposite flank. Mice were treated with 5-fluorouracil to test the sensitivity of tumors to the chemotherapy.
Results: At the end of the first week, the wild type tumors in the mice with Par-4 tumors also were 1.8-fold smaller (p=0) than those tumors in mice who received only wild type tumor cell injections. Over the course of three weeks, the wild type tumors growing in mice without Par-4 tumors increased in volume 12-fold more than those wild type tumors growing in mice with Par-4 tumors. In addition, in the event that Par-4 tumors resolved completely (5% of the cases) the wild type tumors in those mice showed increased growth rates. This data suggests that overexpression of Par-4 in tumor cells in vivo not only sensitized those cells to chemotherapy, but had a bystander effect on tumor cells growing distally to the Par-4 overexpressing cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1209.
Abstract 1216: The mechanism related to anti-apoptotic property of SOX2 in prostate cancer
Authors: Jia Xianpei , Li Xuefei , Mou Wenjun , Zhang Shu , Tan Xiaoyue , Liu Cheng-Hu , Xiang Rong , Li Na 
Published: February 2011

Abstract
SOX2 is one of the key regulatory genes to maintain the pluripotency and unlimited cell growth properties in embryonic stem cells. Recently, more and more researches on cancer stem cell (CSC) support the hypothesis that CSC is the progenitor of cancer cells and contributes to the chemoresistant properties of cancer cells. Although previous study showed SOX2 contributed to the tumorigenic properties in breast and gastric tumor, its function in prostate cancer and apoptosis are still largely unknown. In this study, we used immunohistochemistry method to analyze the expression of SOX2 in prostate cancer tissues and found that the degree of SOX2 staining increased when the Gleason histological grade went higher. We further investigate SOX2's function in cell growth and apoptosis process by using human prostate cancer cells-DU145 with SOX2 overexpression or down-regulation by shRNA. We found that SOX2 increased cell growth and the percentage of cells in S phase in cell cycle assay, it also increased the apoptosis resistant properties of DU145 with reduced mRNA expression of Orai1, STIM1 and decreased store-operated Ca2+ entry (SOCE) activity and cytosolic Ca2+ concentration. This study first investigated SOX2's function in apoptosis process of prostate cancer and elucidated SOX2's regulatory effect on SOCE activity. Our study supports the concept that targeting SOX2 to increase the SOCE activity may be a potential strategy in prostate cancer therapy.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1216.
Abstract 1223: Fibronectin induced lung cancer cell proliferation is dependent on induction of ILK through integrin B1-mediated activation of p38 MAPK and PI3-K
Authors: Sun XiaoJuan , Ritzenthaler Jeffrey D. , Zhong XiaoRong , Roman Jesse , Han Shouwei 
Published: February 2011

Abstract
Fibronectin is a multi-functional matrix glycoprotein protein that has been linked to tumor progression. We previously demonstrated that cellular fibronectin (cFN) increased non-small cell lung carcinoma (NSCLC) cell growth through signals mediated by the integrin α5β1. Here, we explore the role of integrin-linked kinase (ILK), an integrin β1 subunit cytoplasmic domain interactor in cFN induced cell growth. We found that cFN increases ILK expression and kinase activity, promotes protein-protein interactions between ILK and integrin β1. Silencing of ILK attenuated the effect of cFN on cell proliferation. Knockdown of the integrin β1 subunit, but not the integrin α5, blocked the effect of cFN on ILK expression. In addition, the inhibitor of p38MAPK, SB239063, and the inhibitor of PI3-K, wortmannin, abrogated the effect of cFN on ILK expression, whereas the inhibitor of ERK, PD98059, had no effect. Taken together, our results demonstrate that fibronectin induces the expression of ILK through integrin β1-mediated signals that include p38 MAPK and PI3-K. This in turn, promotes lung carcinoma cell proliferation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1223.
Abstract 1228: HOXB13 promotes androgen independent growth of prostate cancer cells by the activation of E2F signaling
Authors: Kim Young-Rang , Oh Kyung-Jin , Choi Chan , Kim Min Soo , Kang Taek Won , Jung Chaeyong 
Published: February 2011

Abstract
Androgen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained. In this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling. Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1228.
Abstract 1231: Nuclear Factor I family members interact with FoxA1 to regulate androgen responsive promoters
Authors: Boachie Adu M. , Degraff David , Yu Xiuping , Sun Qian , Friedman David , Gronostajski Richard , Matusik Robert 
Published: February 2011

Abstract
Forkhead (Fox) proteins are an important class of transcription factors (TFs) that act as molecular “pioneers” by increasing chromatin accessibility. The ability of FoxA1 to act in this manner allows for the subsequent nucleation of responsive promoters by additional, tissue specific TFs, allowing for gene regulation. Our laboratory has previously shown that FoxA1 interacts directly with the androgen receptor (AR), and that the expression of FoxA1 is essential for normal prostate maturation and differentiation. Thus, the ability of FoxA1 to enter a transcriptional complex with AR and other TFs contributes to tissue-specific gene expression in the prostate, and determining the components of FoxA1/AR TF complexes will identify additional targets for the treatment of castrate-resistant PCa.
In order to identify additional proteins that interact with FoxA1, we ectopically expressed dual-affinity tagged FoxA1 in the human PCa cell line LNCaP. Following tandem purification and mass spectrometric analysis, we identified several FoxA1-interacting proteins, including Nuclear Factor I x (NFIx). NFIx is a member of the Nuclear Factor family of TFs, consisting of NFIa, NFIb, NFIc, and NFIx. Co-immunoprecipitation studies verify that NFI family members interact with FoxA1, and Chromatin immunoprecipitation (ChIP) experiments indicate NFI family members bind to androgen regulated, prostate-specific promoters. Finally, transient transfection experiments indicate that NFI family members modulate the androgenic stimulation of the Probasin and PSA promoters both in the presence and absence of FoxA1.
In summary, we have identified NFIx as a novel FoxA1 interacting protein. NFI family members act to modulate the transcriptional activity of FoxA1 and AR on prostate-specific target promoters.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1231.