bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1408: The insulin-like growth factor receptor I and Pyk2 kinase are up-regulated in urothelial carcinomas and promote motility and invasion of urothelial carcinoma-derived cells
Authors: Genua Marco , Xu Shi-Qiong , Gomella Leonard G. , Iozzo Renato V. , Morrione Andrea 
Published: June 2012

Abstract
The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial-carcinoma-derived cells. Significantly, IGF-IR activation did not affected cell proliferation, suggesting that the IGF-IR may play a more prominent role in promoting the transition to the invasive phenotype in bladder cancer.
In this study we demonstrated by immunohistochemical analysis that the IGF-IR expression increased with grade in bladder cancer tissues compared to non-malignant controls. Increased IGF-IR expression in non-tumorigenic T24 urothelial carcinoma cells promoted anchorage independent growth, while targeting of endogenous IGF-IR by shRNA approaches in metastatic T24T cells inhibited colony formation in soft-agar. We also discovered that the focal adhesion protein Pyk2 kinase is activated by IGF-I in urothelial carcinoma-derived cells. Using siRNA approaches, we demonstrated that Pyk2 is critical for IGF-IR-dependent motility and invasion of urothelial cancer cells. In addition, Pyk 2 is critical for IGF-I-dependent activation of the Akt and MAPK pathways, which are critical in the regulation of motility and invasion.
Using immunofluorescence and AQUA (Automated Quantitative Analysis) analysis we also discovered that Pyk2 is overexpressed in bladder cancer tissues compared to normal tissue controls. In urothelial carcinoma-derived tissues there is also increased Pyk2 localization in the nucleus compared to normal tissue controls.
Our results provide the first evidence for a role of the IGF-IR and Pyk2 in motility and invasion of bladder cancer cells, and support the hypothesis that the IGF-IR and Pyk2 may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR and Pyk2 could represent novel molecular targets in bladder cancer and could also serve as a novel tumor biomarkers for diagnosis and possibly prognosis of bladder tumors.
This work has been supported by the Benjamin Perkins Bladder Cancer Fund, the Martin Greitzer Fund and National Institutes of Health Grants RO1 DK068419 (A.M.) and RO1 CA39481 and RO1 CA047282 (R.V.I.).
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 1408. doi:10.1158/1538-7445.AM2011-1408
Abstract 141: miR520d-3p regulates EphA2 and inhibits ovarian cancer growth
Authors: Nishimura Masato , Jung Eun-Jung , Spizzo Riccardo , Shahzad Mian M.K. , Matsuo Koji , Bottsford-Miller Justin , Stone Rebecca L. , Nick Alpa M. , Lu Chunnhua , Han Hee-Dong , Jennings Nicholas B. , Calin George A. , Sood Anil K. 
Published: June 2012

Abstract
EphA2 is a receptor tyrosine kinase that is over-expressed in various malignancies including ovarian cancer. EphA2 is known to promote tumor growth, however its regulation is not well understood. On the basis of data available from The Cancer Genome Atlas, we predicted that miR520d-3p would be a potent inhibition of EphA2. To investigate interaction between miR520d-3p and EphA2, we first examined the mRNA level of these genes in 123 tumors of ovarian cancer patients. There was an inverse correlation between miR520d-3p level and EphA2 mRNA levels (p&lt;0.001); and the prognosis of patients with high miR520d-3p expression was significantly better than those with low miR520d-3p (p&lt;0.001). Next, we established stable clones over-expressing miR520d-3p in HeyA8 and SKOV3ip1 ovarian cancer cells, in which baseline EphA2 levels are high. Compared with parental cell and clones transfected empty vector, EphA2 protein levels were decreased by ∼60%. MiR520d-3p transfection also resulted in significantly decreased migration and invasion in vitro and tumor growth in vivo in orthotopic mouse models. Tumor with high miR520d-3p had decreased EphA2 levels and decreased microvessel density (p&lt;0.01). In conclusion, miR520d-3p is a key regulator of EphA2 levels and may represent a novel therapeutic approach.
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 141. doi:10.1158/1538-7445.AM2011-141
Abstract 1419: Role of p70S6K in breast cancer recurrence
Authors: Belletti Barbara , Sonego Maura , Berton Stefania , Perin Tiziana , Massarut Samuele , Baldassarre Gustavo 
Published: June 2012

Abstract
In Early Breast Cancer (EBC) a single dose of intraoperative radiotherapy with TARGIT (Targeted Intraoperative RadioTherapy) protocol is as effective as the standard therapy in the control of local recurrences (Vaidya et al. Lancet, 376: 91-102, 2010). We recently demonstrated that TARGIT treatment affects the tumor microenvironment, after breast conserving surgery, by altering the local production of several growth factors and cytokines. Eventually, these changes in the proteomic profile, result in a lower activation of the p70S6K pathway in breast cancer cells (Belletti et al. CCR, 14: 1325-32, 2008).
To dissect the role of p70S6K in breast cancer cells proliferation, motility and invasion, we generated genetically modified human breast cancer cell lines expressing specific shRNA or carrying a dominant negative form of p70S6K (p70KR) and tested their ability to grow and migrate, first in vitro then in vivo. Growth curve experiments on MDA MB 231 and MDA MB 453 mammary carcinoma cells, demonstrated that expression of the p70KR mutant slightly reduced the growth rate of these cells. The same cells have been also characterized for their ability to migrate in 2D- and 3D-contexts, in response to the wound fluids harvested from EBC patients as chemoattractants, showing that p70KR reduced their ability to invade. Next, we moved to an in vivo model to evaluate more in detail the involvement of p70S6K in the local recurrence of breast cancer. To this aim, parental or p70S6K genetically modified breast cancer cells have been injected in female nude mice mammary fat pads. Two weeks later, the tumor was removed by surgical excision and the mice observed for the appearance of recurrences. Macroscopic and histo-pathological examination of the primary tumors revealed that despite formation of similar masses, only tumors derived from parental cells displayed lymph-vascular invasion. More importantly, only mammary pads injected with parental cells developed recurrent disease and, at pathological analysis, displayed nodal metastasis. Altogether these data highlight a crucial function of p70S6K in the formation of local recurrence in breast cancers, and support the hypothesis that, in EBC patients, an anti-p70S6K specific therapy may be useful for the prevention of local recurrences.
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 1419. doi:10.1158/1538-7445.AM2011-1419
Abstract 1426: Cyclooxygenase-2 (COX-2) utilizes Jun N-terminal kinases to induce invasion but not tamoxifen resistance in MCF-7 breast cancer cells
Authors: Gonzalez-Villasana Vianey , Nieves-Alicea Rene , McMurtry Vanity , Huaringa Armando , Simeone Ann-Marie , Gutierrez-Puente Yolanda , Lopez-Berestein Gabriel , Tari Ana M. 
Published: June 2012

Abstract
Elevated Cyclooxygenase-2 (COX-2) expression in breast tumors had been associated with a lower survival rate in patients with Estrogen Receptor α (ERα)-positive tumors. We propose that COX-2 reduces survival rate in breast cancer patients with ERα-positive tumors because COX-2 decreases tamoxifen sensitivity and increases invasive activity of breast cancer cells. We demonstrated that transfection of the COX-2 gene in the tamoxifen-sensitive, ERα-positive MCF-7 breast cancer cell line decreased the cells’ sensitivity to tamoxifen by about 5-fold, and increased their invasive activity by about 3-fold. Furthermore, we demonstrated that COX-2 utilizes PGE2 to activate Protein Kinase C (PKC) to induce these tumorigeneic effects. However, which downstream factors are recruited by the COX-2/PGE2/PKC pathway to induce tamoxifen resistance and breast cancer cell invasion are not known. Here we report that COX-2 increases the phosphorylation of Jun N-terminal kinase (JNK), but not that of extracellular signal regulated kinases (ERK1,2), p38 mitogen activated protein kinase, or Akt. Inhibition of JNK by a chemical inhibitor or siRNA led to decreased COX-2-mediated invasion. Yet, JNK inhibition did not affect COX-2-mediated tamoxifen resistance. We propose that JNK is a promising target to block invasion in patients whose tumors are ERα-positive and present high levels of COX-2.
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 1426. doi:10.1158/1538-7445.AM2011-1426
Abstract 1439: Clinical significance of KISS1 protein expression in breast cancer metastasis to brain
Authors: Ulasov Ilya V. , Kaverina Natalya , Thaci Bart , Pytel Peter , Sattar Husain , Cao Dingcai , Hurst Douglas R. , Welch Danny R. , Olopade Olufunmilayo I. , Kadagidze Zaira G. , Lesniak Maciej S. 
Published: June 2012

Abstract
Aim: The present study was aimed to investigate whether KISS1 suppressor protein could be used as a prognostic marker in development of breast cancer metastases. Methods: To test whether breast cancer brain metastases (BMHB) have altered expression of KISS1, we created a TMA (tissue microarray) recipient block containing 136 specimens: 103 specimens of primary breast cancer cells (invasive ductal carcinoma, IDC), 7 specimens from draining lymph nodes (LN), 39 brain metastases and 14 samples of normal breast tissue (NBreast). Each core was duplicated. Sections from this block were stained with antibodies that recognize KISS1. Immunoassays were graded based on: A) intensity of immunoreactive cells staining (Negative, 0% of the cells have staining; 1+, 5-20% of total cells have staining (Mild); 2+, 20-50% of total cells have staining (Moderate); 3+, 50% or more of total cells have staining(High)) and B) score calculated by ACIS system (Chromavision/Clarient, Aliso Viejo, CA). Positive staining in the present study was defined as visibility at low magnification (10x) and was confirmed by two pathologists. To validate the IHC findings, relative expression of KISS1 was evaluated by real time PCR technique. Results: Based on TMA expression results, we found that breast cancer metastases exhibited statistically significant less KISS1 expression vs. primary specimens (Kruskal-Wallis p value = 0.011). In validation set, 84.2% of IDC samples had either moderate (38/76) or high (26/76) expression of KISS1 protein whereas weak (negative or mild) expression was observed in 15.8% cases (12/76). In contrast, metastatic cases demonstrated weak expression in 100% cases (19/19). The real time PCR data confirmed IHC findings. We analyzed the correlation between the level of KISS1 expression and breast cancer prognosis based on the IHC data. The group of patients with high expression of KISS1 protein (1x and more) was found to have a trend toward slower disease progression. Those patients developed brain metastases 51.0+15.0 (CI: 17.7-84.3) months after tumor resection whereas the group of patients with no KISS1 expression had metastases after only 27.0+4.93 (CI: 15.39-38.69) months. Conclusions: These results suggest that high level of KISS1 protein expression is advantageous for breast cancer patients and that low levels correlate with metastases towards secondary organs such as brain.
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 1439. doi:10.1158/1538-7445.AM2011-1439
Abstract 1442: Expression of miRNA processing factor Dicer in cutaneous melanoma and its role in cell invasion
Authors: Shourkaei Seyed Mehdi Jafarnejad , Ghaffari Mazyar , Martinka Magdalena , Cox Michael , Li Gang 
Published: June 2012

Abstract
Deregulated expression of miRNAs is a hallmark of various human cancers. One potential mechanism for the aberrant expression of miRNAs in cancers is their abnormal processing due to altered expression or function of their processing factors such as Dicer and Drosha. Although altered expression of several miRNAs have been reported in melanoma, the expression profile of miRNA processing factors in this cancer is unknown. In this study we examined the expression of Dicer protein in different stages of melanocytic lesions. Using tissue microarray and immunohistochemistry, we evaluated cytoplasmic Dicer expression in 32 dysplastic nevi, 77 primary melanomas, and 48 metastatic melanomas. Our data revealed that expression of Dicer has a significant but inverse correlation with progression of melanoma (P &lt; 0.001). Accordingly, the number of samples with moderate-strong staining for Dicer was reduced from 81.2% in dysplastic nevi to 67.5% in primary melanoma and 40.8% in metastatic melanoma. The expression of Dicer was also negatively correlated with the American Joint Committee on Cancer (AJCC) staging of the melanoma samples (p=0.019). Moreover, the reduced Dicer expression was correlated with a poorer disease-specific 5-year survival of melanoma patients (P = 0.026). Multivariate Cox regression analysis revealed that reduced nuclear Dicer expression is an independent prognostic factor to predict patient outcome (P = 0.030). We also knocked down Dicer expression and used Boyden chamber migration assay to study its role in the invasion ability of MMRU human melanoma cells. Interestingly, knockdown of Dicer enhanced the invasion ability of MMRU cells by 2-fold. Our results demonstrate the critical role of miRNA machinery in the progression of melanoma, suggesting that Dicer may be a suitable prognostic marker for human melanoma patients as well as a potential therapeutic target.
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 1442. doi:10.1158/1538-7445.AM2011-1442
Abstract 1444: Semaphorin 6A inhibits the cell migration in lung adenocarcinoma cells
Authors: Cheng-Ying Shen , Yung-Hua Li , Tzu-Pin Lu , Liang-Chuan Lai , Y Chuang Eric , Mong-Hsun Tsai 
Published: June 2012

Abstract
In Taiwan, most of the female lung cancer patients are non-smokers (&gt;90%) and most of the tumor types are adenocarcinoma. In order to discover novel molecular targets for the non-smoking female lung cancer patients in Taiwan, the paired normal and tumor lung tissues were collected from 56 female non-smoking lung cancer patients for microarray analysis. The results showed that several genes in the semaphorin family, including SEMA6A, were significantly down-regulated in the tumor tissues by Affymetrix analysis. Semaphorins are a protein family that defined into 8 different classes of protein. Semaphorin classes 3 through 7 are found in vertebrates and the classes 4 through 6 are transmembrane proteins. The semaphorin proteins have shown to play important roles in the axon guidance of the central nervous system (CNS) and peripheral nervous system (PNS). Although originally characterized as axonal guidance molecules, several studies have indicated that the semaphorins can regulate tumor growth and tumor metastasis. However, the specific mechanisms of SEMA6A in the lung cancer cells are still unclear. Therefore, the novel functions of SEMA6A in the lung cancer cells are further studied. First, the expression levels of SEMA6A in the lung cancer tissues were validated by quantitative real-time PCR and immunohistochemistry and the results showed significant down-regulation in the tumor tissues. In addition, the non-small lung cell lines, A549 and H1299, were used to further investigate the function of SEMA6A. The A549 and H1299 cells with overexpressed SEMA6A were identified and the cell membrane fraction was purified for western blot analysis. The results showed that both of the cells did not express SEMA6A proteins. Furthermore, the result of wound healing assay was shown that the A549 and H1299 cells with overexpressed SEMA6A exhibited a lower capacity to fill the gap during 24 hours incubation compared to the cells without SEMA6A overexpression. The results of transwell migration assay also showed that the A549 and H1299 cells with overexpressed SEMA6A, bur not the A549 and H1299 cells, decrease the migration ability. Our data indicated that normal lung tissues expressed more SEMA6A protein which might inhibit the migration than the cancer lung tissues. The SEMA6A receptor, plexin-A2, will be further investigated the downstream regulation of SEMA6A. In summary, our data indicated that SEMA6A could be an important factor in lung tumorgenesis.
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 1444. doi:10.1158/1538-7445.AM2011-1444
Abstract 1455: Novel role for the metastasis suppressor NM23-H1 in suppression of transendothelial migration toward CXCL12 gradient
Authors: Novak Marián , Kaetzel David M. 
Published: June 2012

Abstract
Expression of the metastasis suppressor NM23-H1 is inversely correlated with the stage of tumor progression and metastasis in several leading malignancies including melanoma. Although multiple enzymatic activities and protein interactions have been described for this molecule, the precise mechanism by which NM23-H1 suppresses metastasis remains unknown. Metastasis of highly malignant cells toward their metastatic niche is facilitated by chemokine gradients which also guide specific populations of hematopoietic progenitor cells during their differentiation. One of the major homing factors for differentiating hematopoietic cells, as well as organospecific metastasis of melanoma cells is CXCL12 (SDF-1). Our previous in vivo tumor explant assays indicated that NM23-H1 suppresses dissemination of tumor cells from the primary site and their entry into or departure from circulation. Herein, we report that forced expression of NM23-H1 in the NM23-H1-deficient and highly invasive melanoma cell lines WM793 and 1205LU potently suppressed their ability to undergo transendothelial migration toward a CXCL12 gradient. Furthermore, we saw a dose-dependent increase in adhesion of NM23-H1 deficient cells to endothelia following the exposure to CXCL12, a process that was effectively blocked by forced expression of NM23-H1. We are currently investigating the molecular and signaling events triggered in melanoma models upon exposure to CXCL12 in order to determine the precise molecular mechanisms through which NM23-H1 disrupts CXCL12 mediated tumor cell dissemination. Our preliminary analysis of downstream signaling from the cognate receptor for CXCL12, CXCR4, indicate delayed kinetics of Akt phosphorylation in NM23-H1-expressing 1205LU cells as compared to their NM23-H1-deficient counterparts. Although NM23-H1 has been previously described as a negative regulator of the small GTPases Rac1 and Cdc42, their activation was unaffected by NM23-H1 status in 1205LU cells. These preliminary results suggest a novel role for NM23-H1 in regulating CXCL12 signaling in suppression of transendothelial migration, a critical step in melanoma metastasis
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 1455. doi:10.1158/1538-7445.AM2011-1455
Abstract 1458: Arid4b: A germline breast cancer progression modifier gene
Authors: Winter Scott F. , Hunter Kent W. 
Published: June 2012

Abstract
Our laboratory's research focuses on the role of host genetics in breast cancer metastasis. The MMTV-PyMT transgenic mouse model exhibits varying metastatic efficiency to the lungs when transgenic mice in an FVB background are bred to other strains such as DBA and AKR. Combining quantitative measurement of metastasis with genetic mapping studies of the AKXD recombinant inbred panel of mice has allowed us to determine quantitative trait loci (QTLs) that affect metastatic efficiency. My work has focused on the potential role of Arid4b in breast cancer tumorigenesis and metastasis. Arid4b is a component of the mSin3a histone deacetylase complex, which has an established role in breast cancer progression, and Arid4b is a candidate gene underlying a metastasis QTL peak we have identified on mouse chromosome 13. Sequencing revealed a high density of non-synonymous SNPs between the AKR and DBA alleles in exon 22, which encodes a C-terminal region of the Arid4b protein that is known to mediate interaction with the mSin3a HDAC complex. We have recently discovered that Arid4b binds another protein that our laboratory has implicated in metastasis susceptibility, the transcriptional elongation regulator Bromodomain 4 (Brd4), and we are currently using co-IPs and proteomics strategies such as tandem affinity purification to identify other proteins that may bind differentially to the AKR or DBA Arid4b proteins. In orthotopic implantation assays, cells ectopically expressing the DBA allele of Arid4b formed larger primary tumors compared to cells expressing the AKR allele, and western blots using an Ab specific for dimethylated histone H3 lysine 27 suggest that the mechanism of Arid4b action may involve modification of chromatin structure. Arid4b is also alternately spliced, and a second isoform lacks part of a conserved Chromo domain that is predicted to bind methylated histone tails. We are currently investigating the consequences of ectopic expression of the multiple alleles and isoforms of Arid4b in vivo using orthotopic implantation assays. It is likely that both the alternate splicing of the Chromo domain and the allelic variation in the C-terminal domain modulate an epigenetic influence of Arid4b on tumorigenesis and metastasis.
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 1458. doi:10.1158/1538-7445.AM2011-1458