bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hormone-Induced Protection against Mammary Tumorigenesis Is Conserved in Multiple Rat Strains and Identifies a Core Gene Expression Signature Induced by Pregnancy
Authors: Blakely Collin M. , Stoddard Alexander J. , Belka George K. , Dugan Katherine D. , Notarfrancesco Kathleen L. , Moody Susan E. , D'Cruz Celina M. , Chodosh Lewis A. 
Published: June 2006

AbstractWomen who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-β signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer. (Cancer Res 2006; 66(12): 6421-31)
YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases
Authors: Yeo Eun-Jin , Ryu Ji-Hye , Chun Yang-Sook , Cho Young-Suk , Jang In-Jin , Cho HoSung , Kim Jinho , Kim Myung-Suk , Park Jong-Wan 
Published: June 2006

Abstract
Hypoxia-inducible factor-1α (HIF-1α) seems central to tumor growth and progression because it up-regulates genes essential for angiogenesis and the hypoxic adaptation of cancer cells, which is why HIF-1α inhibition is viewed as a cancer therapy strategy. Paradoxically, HIF-1α also leads to cell cycle arrest or the apoptosis of cancer cells. Thus, the possibility cannot be ruled out that HIF-1α inhibitors unlock cell cycle arrest under hypoxic conditions and prevent cell death, which would limit the anticancer effect of HIF-1α inhibitors. Previously, we reported on the development of YC-1 as an anticancer agent that inhibits HIF-1α. In the present study, we evaluated the effects of YC-1 on hypoxia-induced cell cycle arrest and cell death. It was found that YC-1 does not reverse the antiproliferative effect of hypoxia, but rather that it induces S-phase arrest and apoptosis at therapeutic concentrations that inhibit HIF-1α and tumor growth; however, YC-1 did not stimulate cyclic guanosine 3′,5′-monophosphate production in this concentration range. It was also found that YC-1 activates the checkpoint kinase–mediated intra-S-phase checkpoint, independently of ataxia-telangiectasia mutated kinase or ataxia-telangiectasia mutated and Rad3-related kinase. These results imply that YC-1 does not promote the regrowth of hypoxic tumors because of its cell cycle arrest effect. Furthermore, YC-1 may induce the combined anticancer effects of HIF-1α inhibition and cell growth inhibition. (Cancer Res 2006; 66(12): 6345-52)
Mutant p53 Induces the GEF-H1 Oncogene, a Guanine Nucleotide Exchange Factor-H1 for RhoA, Resulting in Accelerated Cell Proliferation in Tumor Cells
Authors: Mizuarai Shinji , Yamanaka Kazunori , Kotani Hidehito 
Published: June 2006

Abstract
The tumor suppressor gene p53 is known to induce G1-S and G2-M cell cycle arrest and apoptosis by transactivating various wild-type (WT) p53 regulatory genes. Mutational inactivation of p53 is detected in more than half of human cancers, depriving the p53 protein of its tumor-suppressive functions. Recent studies have shown that mutant p53 provides tumor cells with gain-of-function properties, such as accelerated cell proliferation, increased metastasis, and apoptosis resistance. However, the mechanism underlying the elevated tumorigenicity by p53 mutation remains to be elucidated. In the present study, we showed that GEF-H1, a guanine exchange factor-H1 for RhoA, is transcriptionally activated by the induction of mutant p53 proteins, thereby accelerating tumor cell proliferation. Osteosarcoma U2OS cell lines, which express inducible p53 mutants (V157F, R175H, and R248Q), were established, and the expression profiles of each cell line were then analyzed to detect genes specifically induced by mutant p53. We identified GEF-H1 as one of the consensus genes whose expression was significantly induced by the three mutants. The GEF-H1 expression level strongly correlated with p53 status in a panel of 32 cancer cell lines, and GEF-H1 induction caused activation of RhoA. Furthermore, growth of mutant p53 cells was dependent on GEF-H1 expression, whereas that of WT p53 cells was not. These results suggest that increased GEF-H1 expression contributes to the tumor progression phenotype associated with the p53 mutation. (Cancer Res 2006; 66(12): 6319-26)
The Epithelial Cell Transforming Sequence 2, a Guanine Nucleotide Exchange Factor for Rho GTPases, Is Repressed by p53 via Protein Methyltransferases and Is Required for G1-S Transition
Authors: Scoumanne Ariane , Chen Xinbin 
Published: June 2006

Abstract
The epithelial cell transforming sequence 2 (ECT2), a member of the Dbl family of guanine nucleotide exchange factor for Rho GTPases, is required for cytokinesis. The tumor suppressor p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest and apoptosis, in response to stress signals. Here, we showed that ECT2 is negatively regulated by wild-type p53 but not tumor-derived mutant p53 or other p53 family members. In addition, ECT2 is down-regulated in multiple cell lines by DNA damage agents and Nutlin-3, an MDM2 antagonist, in a p53-dependent manner. We also showed that the activity of the ECT2 promoter is repressed by wild-type p53, and to a lesser extent, by p21. In addition, the second activation domain in p53 is necessary for the efficient repression of ECT2. Importantly, we found that the ECT2 gene is bound by p53 in vivo in response to DNA damage and Nutlin-3 treatment. Furthermore, we provided evidence that inhibition of protein methyltransferases, especially arginine methyltransferases, relieve the repression of ECT2 induced by DNA damage or Nutlin-3 in a p53-dependent manner. Finally, we generated multiple cell lines in which ECT2 is inducibly knocked down and found that ECT2 knockdown triggers cell cycle arrest in G1. Taken together, we uncovered a novel function for ECT2 and provided a novel mechanism by which p53 represses gene expression via protein methyltransferases. (Cancer Res 2006; 66(12): 6271-9)
Tumor Growth Suppression in Pancreatic Cancer by a Putative Metastasis Suppressor Gene Cap43/NDRG1/Drg-1 through Modulation of Angiogenesis
Authors: Maruyama Yuichiro , Ono Mayumi , Kawahara Akihiko , Yokoyama Toshiro , Basaki Yuji , Kage Masayoshi , Aoyagi Shigeaki , Kinoshita Hisafumi , Kuwano Michihiko 
Published: June 2006

Abstract
Cap43 has been identified as a nickel- and calcium-induced gene, and is also known as N-myc downstream-regulated gene 1 (NDRG1), Drg-1 and rit42. It is also reported that overexpression of Cap43 suppresses metastasis of some malignancies, but its precise role remains unclear. In this study, we asked how Cap43 could modulate the tumor growth of pancreatic cancer. Stable Cap43 cDNA transfectants of pancreatic cancer cells with Cap43 overexpression showed similar growth rates in culture as their control counterparts with low Cap43 protein level. By contrast, Cap43 overexpression showed a marked decrease in tumor growth rates in vivo. Moreover, a marked reduction in tumor-induced angiogenesis was observed. Gelatinolytic activity by matrix metalloproteinase-9 and invasive ability in Matrigel invasion activity were markedly decreased in pancreatic cancer cell lines with high Cap43 expression. Cellular expression of matrix metalloproteinase-9 and two major angiogenic factors, vascular endothelial growth factor and interleukin-8, were also significantly decreased in cell lines with Cap43 overexpression as compared with their parental counterparts. Immunohistochemical analysis of specimens from 65 patients with pancreatic ductal adenocarcinoma showed a significant association between Cap43 expression and tumor microvascular density (P = 0.0001) as well as depth of invasion (P = 0.0003), histopathologic grading (P = 0.0244), and overall survival rates for patients with pancreatic cancer (P = 0.0062). Thus, Cap43 could play a key role in the angiogenic on- or off-switch of tumor stroma in pancreatic ductal adenocarcinoma. (Cancer Res 2006; 66(12): 6233-42)
NFKB1 Is a Direct Target of the TAL1 Oncoprotein in Human T Leukemia Cells
Authors: Chang Pei-Yun , Draheim Kyle , Kelliher Michelle A. , Miyamoto Shigeki 
Published: June 2006

Abstract
We recently showed that a subset of human T acute lymphoblastic leukemia (T-ALL) cell lines expresses low basal levels of p50, a nuclear factor-κB (NF-κB)/Rel family member, resulting in their capacity to activate the atypical p65:cRel complex rather than the classic p50:p65 dimer. Here, we show that the transcription factor TAL1 (also known as SCL) binds to the promoter of the NFKB1 gene that encodes p50 and represses its transcription to set up this unique response in T-ALL cells. When TAL1 expression is reduced in CEM T leukemia cells, basal NFKB1 expression is increased, and the levels of p65:cRel complex and transcription of its target gene, such as intercellular adhesion molecule-1 (ICAM-1), are reduced in response to etoposide treatment. Moreover, a significant negative correlation between NFKB1 and TAL1 or LMO1 was found in primary human TAL1/LMO1 double-positive T-ALL samples previously described by Ferrando et al. Thus, TAL1 modulates NFKB1 expression and an NF-κB-dependent transcriptional program in a subset of human T-cell leukemia cells. (Cancer Res 2006; 66(12): 6008-13)
Changes in Antitumor Response in C57BL/6J-Min/+ Mice during Long-term Administration of a Selective Cyclooxygenase-2 Inhibitor
Authors: Carothers Adelaide M. , Moran Amy E. , Cho Nancy L. , Redston Mark , Bertagnolli Monica M. 
Published: June 2006

Abstract
Selective cyclooxygenase-2 (COX-2) inhibitors are widely prescribed for severe arthritis and are currently under study in human chemoprevention trials. Recently, long-term use of these agents has come under scrutiny due to reports of treatment-associated cardiovascular toxicity. On short-term administration, the selective COX-2 inhibitor celecoxib inhibits adenoma growth in animal tumor models, including the C57BL/6J-Min/+ (Min/+) mouse. With uninterrupted long-term celecoxib administration, intestinal tumors in Min/+ mice initially regressed and then recurred to levels comparable with untreated controls. Celecoxib treatment initially suppressed COX-2 and prostaglandin E2 (PGE2) expression, but long-term use produced significantly higher levels of these molecules and reactivated PGE2-associated growth factor signaling pathways in tumor and normal tissues. These results indicate that COX-2 is an important chemoprevention target and that inhibition of this enzyme alters a paracrine enterocyte regulatory pathway. Chronic uninterrupted celecoxib treatment, however, induces untoward effects that enhance early progression events in intestinal tumorigenesis and may contribute to treatment toxicity. (Cancer Res 2006; 66(12): 6432-8)
Carcinoembryonic Antigen–Targeted Selective Gene Therapy for Gastric Cancer through FZ33 Fiber-Modified Adenovirus Vectors
Authors: Tanaka Toshihiro , Huang Jianhua , Hirai Sachie , Kuroki Motomu , Kuroki Masahide , Watanabe Naoki , Tomihara Kei , Kato Kazunori , Hamada Hirofumi 
Published: June 2006

AbstractPurpose: A major problem when using the adenoviral vectors for gene therapy applications is thought to be related to low transduction efficiency in cancer cells or to side effects in normal cells. There is an urgent requirement to improve the specificity of gene delivery in the context of cancer gene therapy.Experimental Design: We constructed a genetically modified adenovirus incorporating an IgG Fc-binding motif from the Staphylococcus protein A, Z33, within the HI loop (Adv-FZ33). A remarkable degree of targeted gene delivery to gastric cancer cells was obtained with Adv-FZ33 with the fully human anti–carcinoembryonic antigen (CEA) monoclonal antibody, C2-45.Results: In vitro LacZ or EGFP gene expression after Adv-FZ33 infection via C2-45 was 20 times higher than control monoclonal antibody in MKN-45 at 1,000 viral particles/cell. We generated Ax3CAUP-FZ33 (UP-FZ33), which is an Adv-FZ33 derivative vector expressing a therapeutic gene (i.e., Escherichia coli uracil phosphoribosyltransferase), which converts 5-fluorouracil (5-FU) directly to 5-fluoro-UMP. UP-FZ33 with C2-45 enhanced the cytotoxicity of 5-FU by 10.5-fold in terms of IC50 against MKN-45 compared with control IgG4. In a nude mouse peritoneal dissemination model, tumor growth in mice treated with UP-FZ33/C2-45/5-FU was significantly suppressed, and tumor volumes were less than one-fourth of those of the control IgG4 group (P &lt; 0.05). The median survival time of the UP-FZ33/C2-45/5-FU group was significantly longer than those treated with PBS or 5-FU only (P &lt; 0.01).Conclusions: These data suggest that CEA-targeted FZ33 mutant adenovirus-mediated gene delivery offers a strong and selective therapeutic modality against CEA-producing cancers.
Roles of KLF6 and KLF6-SV1 in Ovarian Cancer Progression and Intraperitoneal Dissemination
Authors: DiFeo Analisa , Narla Goutham , Hirshfeld Jennifer , Camacho-Vanegas Olga , Narla Jyothsna , Rose Stephen L. , Kalir Tamara , Yao Shen , Levine Alice , Birrer Michael J. , Bonome Tomas , Friedman Scott L. , Buller Richard E. , Martignetti John A. 
Published: June 2006

AbstractPurpose: We investigated the role of the KLF6 tumor suppressor gene and its alternatively spliced isoform KLF6-SV1 in epithelial ovarian cancer (EOC).Experimental Design: We first analyzed tumors from 68 females with EOC for KLF6 gene inactivation using fluorescent loss of heterozygosity (LOH) analysis and direct DNA sequencing and then defined changes in KLF6 and KLF6-SV1 expression levels by quantitative real-time PCR. We then directly tested the effect of KLF6 and KLF6-SV1 inhibition in SKOV-3 stable cell lines on cellular invasion and proliferation in culture and tumor growth, i.p. dissemination, ascites production, and angiogenesis in vivo using BALB/c nu/nu mice. All statistical tests were two sided.Results: LOH was present in 59% of samples in a cell type–specific manner, highest in serous (72%) and endometrioid (75%) subtypes, but absent in clear cell tumors. LOH was significantly correlated with tumor stage and grade. In addition, KLF6 expression was decreased in tumors when compared with ovarian surface epithelial cells. In contrast, KLF6-SV1 expression was increased ∼5-fold and was associated with increased tumor grade regardless of LOH status. Consistent with these findings, KLF6 silencing increased cellular and tumor growth, angiogenesis, and vascular endothelial growth factor expression, i.p. dissemination, and ascites production. Conversely, KLF6-SV1 down-regulation decreased cell proliferation and invasion and completely suppressed in vivo tumor formation.Conclusion: Our results show that KLF6 and KLF6-SV1 are associated with key clinical features of EOC and suggest that their therapeutic targeting may alter ovarian cancer growth, progression, and dissemination.
Genetic and Epigenetic Analysis of the Putative Tumor Suppressor km23 in Primary Ovarian, Breast, and Colorectal Cancers
Authors: Campbell Ian G. , Phillips Wayne A. , Choong David Y.H. 
Published: June 2006

Abstract
Purpose: A very high frequency of somatic mutations in the transforming growth factor-β signaling component km23 has been reported in a small series of ovarian cancers (8 of 19, 42%). Functional studies showed that some mutations disrupt km23 function, resulting in aberrant transforming growth factor-β signaling and presumably enhanced tumorigenicity. If verified, this would elevate mutation of km23 as the single most frequent somatic event in ovarian cancer.
Experimental Design: We sought to verify the frequency of silencing of km23 among 104 primary ovarian cancers (49 serous, 18 mucinous, 29 endometrioid/clear cell, and 8 undifferentiated) as well as 72 breast and 61 colorectal cancers by undertaking both somatic mutation and promoter methylation analyses. All four exons of km23 were individually amplified from genomic DNA with primers complementary to surrounding intronic sequences and analyzed by single-stranded conformational polymorphism analysis.
Results: Two germ line polymorphisms were identified, but none of the 237 tumors analyzed harbored somatic km23 mutations. In addition, promoter methylation analysis showed that in all cases, the 5′ CpG island was unmethylated.
Conclusions: Our data suggest that silencing of km23, either through somatic genetic mutation or promoter hypermethylation, is rare in ovarian, breast, and colorectal cancers.
Phosphatidylinositol 3-Kinase in the G Protein-Coupled Receptor–Induced Chemokinesis and Chemotaxis of MDA-MB-468 Breast Carcinoma Cells: A Comparison with Leukocytes
Authors: Bastian Philipp , Posch Birte , Lang Kerstin , Niggemann Bernd , Zaenker Kurt S. , Hatt Hanns , Entschladen Frank 
Published: June 2006

Abstract
The polarization of tumor cells and leukocytes into a front end and a rear end is a crucial prerequisite for their autonomous, directed movement. Phosphatidylinositol 3-kinase (PI3K) is assumed to play an important role in this polarization process, whereas the results obtained with different cell types and different migration assays widely vary. Thus, we conducted a comparative study on the role of the PI3K in the locomotor activity and directionality of the migration of tumor cells on the example of MDA-MB-468 breast carcinoma cells in comparison with CTLs and neutrophil granulocytes. We used our well-established, collagen-based, three-dimensional migration assay for the investigation of the chemokinesis and chemotaxis of these cells. Our results show that the role of the PI3K in the regulation of migratory activity is distinct between the investigated cell types: the migration of CTLs and MDA-MB-468 cells was impaired by the inhibition of the PI3K with wortmannin, whereas neutrophil granulocytes were only slightly affected. However, neither cell type was impaired in the ability to respond chemotactically to gradients of ligands to G protein-coupled receptors. Thus, the PI3K contributes to the regulation of migratory activity but not to the directionality of migration of MDA-MB-468 breast carcinoma cells. As a further conclusion with regard to cancer treatment, the PI3K is not a suitable target for the inhibition of metastasis formation, because the migration of leukocytes is also affected, which leads to a dysfunction of the immune defense. (Mol Cancer Res 2006;4(6):411–21)
Roles of Equatorial Waves and Western Boundary Reflection in the Seasonal Circulation of the Equatorial Indian Ocean
Authors: Yuan Dongliang , Han Weiqing 
Published: June 2006

Abstract
An ocean general circulation model (OGCM) is used to study the roles of equatorial waves and western boundary reflection in the seasonal circulation of the equatorial Indian Ocean. The western boundary reflection is defined as the total Kelvin waves leaving the western boundary, which include the reflection of the equatorial Rossby waves as well as the effects of alongshore winds, off-equatorial Rossby waves, and nonlinear processes near the western boundary. The evaluation of the reflection is based on a wave decomposition of the OGCM results and experiments with linear models. It is found that the alongshore winds along the east coast of Africa and the Rossby waves in the off-equatorial areas contribute significantly to the annual harmonics of the equatorial Kelvin waves at the western boundary. The semiannual harmonics of the Kelvin waves, on the other hand, originate primarily from a linear reflection of the equatorial Rossby waves. The dynamics of a dominant annual oscillation of sea level coexisting with the dominant semiannual oscillations of surface zonal currents in the central equatorial Indian Ocean are investigated. These sea level and zonal current patterns are found to be closely related to the linear reflections of the semiannual harmonics at the meridional boundaries. Because of the reflections, the second baroclinic mode resonates with the semiannual wind forcing; that is, the semiannual zonal currents carried by the reflected waves enhance the wind-forced currents at the central basin. Because of the different behavior of the zonal current and sea level during the reflections, the semiannual sea levels of the directly forced and reflected waves cancel each other significantly at the central basin. In the meantime, the annual harmonic of the sea level remains large, producing a dominant annual oscillation of sea level in the central equatorial Indian Ocean. The linear reflection causes the semiannual harmonics of the incoming and reflected sea levels to enhance each other at the meridional boundaries. In addition, the weak annual harmonics of sea level in the western basin, resulting from a combined effect of the western boundary reflection and the equatorial zonal wind forcing, facilitate the dominance by the semiannual harmonics near the western boundary despite the strong local wind forcing at the annual period. The Rossby waves are found to have a much larger contribution to the observed equatorial semiannual oscillations of surface zonal currents than the Kelvin waves. The westward progressive reversal of seasonal surface zonal currents along the equator in the observations is primarily due to the Rossby wave propagation.
Regulation of airway smooth muscle RhoA/ROCK activities by cholinergic and bronchodilator stimuli
Authors: Liu C. , Zuo J. , Janssen L. J. 
Published: June 2006

The current study set out to compare the temporal relationships of Rho activity, Rho kinase (ROCK) activity and tone following cholinergic stimulation in the presence and absence of three different bronchodilators.Bovine trachea challenged with a half-maximally effective concentration of carbachol (CCh) was flash-frozen at different times, then assayed for Rho (rhotekin pull-down assay) and ROCK (Western blot; radiometric assay) activities.Rho was activated within 30 s, followed by ROCK (peak at 2 min); both returned to baseline by 20 min, although tone continued to rise over that period. Increasing the concentration of CCh greatly increased the magnitudes and rates of stimulation of Rho, ROCK and tone. These CCh-induced changes were next compared in tissues pre-treated with isoproterenol, salmeterol or the nitric oxide donorS-nitroso-N-acetylpenicillamine (SNAP). Neither the time course nor the magnitude of Rho-activation were reduced by the β-agonists; SNAP slowed Rho activation but it did not alter the peak magnitude. These observations were mirrored in ROCK activation and contraction. When tissues were pre-constricted with CCh and then challenged with the bronchodilators, however, all three agonists reversed cholinergically stimulated Rho, ROCK and myosin light chain kinase activities as well as tone.In conclusion, bronchodilators can suppress RhoA and Rho kinase activities, although their major effect appears to be on myosin light chain kinase activity.