bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transforming Growth Factor-β, Estrogen, and Progesterone Converge on the Regulation of p27Kip1 in the Normal and Malignant Endometrium
Authors: Lecanda Jon , Parekh Trilok V. , Gama Patricia , Lin Ke , Liarski Vladimir , Uretsky Seth , Mittal Khush , Gold Leslie I. 
Published: February 2007

AbstractHormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-β (TGF-β) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-β–mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 (p27) to arrest cells in G1 phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-β induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-β, which was 2-fold higher in the nuclear fraction; mRNA levels were unaffected. In addition, ECA tissue lysates show a high rate of ubiquitin-mediated degradation of p27 compared with normal secretory-phase endometrial tissue (SE) such that 4% and 89% of recombinant p27 added to the lysates remains after 3 and 20 h, respectively. These results are reflected in vivo as ECA tissue lacks p27 compared with high expression of p27 in SE (P ≤ 0.001). Furthermore, we show that estrogen treatment of EECs causes mitogen-activated protein kinase–driven proteasomal degradation of p27 whereas progesterone induces a marked increase in p27 in both normal EECs and ECA cells. Therefore, these data suggest that TGF-β induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-β cannot induce p27 levels due to dysregulated TGF-β signaling, thereby causing 17β-estradiol–driven p27 degradation to proceed unchecked for cell cycle progression. Thus, p27 may be a central target for growth regulation of normal endometrium and in the pathogenesis of ECA. [Cancer Res 2007;67(3):1007–18]
Long-term Treatment with Tamoxifen Facilitates Translocation of Estrogen Receptor α out of the Nucleus and Enhances its Interaction with EGFR in MCF-7 Breast Cancer Cells
Authors: Fan Ping , Wang Jiping , Santen Richard J. , Yue Wei 
Published: February 2007

Abstract
The therapeutic benefit of tamoxifen in patients with hormone-dependent breast cancer is limited by acquired resistance to this drug. To investigate the biological alterations responsible for tamoxifen resistance, an in vitro model was established. After 6-month continuous exposure to tamoxifen (10−7 mol/L), growth of MCF-7 breast cancer cells was no longer inhibited by this antiestrogen. Although there was no significant increase in the basal levels of activated mitogen-activated protein kinase (MAPK), tamoxifen-resistant (TAM-R) cells exhibited enhanced sensitivity to epidermal growth factor (EGF) and estradiol stimulated activation of MAPK. Tamoxifen elicited rapid phosphorylation of MAPK, in contrast to its antagonistic activity in control cells. Blockade of the EGF receptor (EGFR)/MAPK pathway caused more dramatic inhibition of growth of TAM-R cells than the control cells. An increased amount of estrogen receptor α (ERα) was coimmunoprecipitated with EGFR from TAM-R cells although the total levels of these receptors were not increased. Notably, ERα seemed to redistribute to extranuclear sites in TAM-R cells. Increased ERα immunoreactivity in the cytoplasm and plasma membrane of TAM-R cells was shown by fluorescent microscopy and by Western analysis of isolated cellular fractions. In TAM-R cells, an increased amount of c-Src was coprecipitated with EGFR or ERα. Blockade of c-Src activity resulted in redistribution of ERα back to the nucleus and in reduction of its interaction with EGFR. Prolonged blockade of c-Src activity restored sensitivity of TAM-R cells to tamoxifen. Our results suggest that enhanced nongenomic function of ERα via cooperation with the EGFR pathway is one of the mechanisms responsible for acquired tamoxifen resistance. [Cancer Res 2007;67(3):1352–60]
Genetic Variation in Base Excision Repair Genes and the Prevalence of Advanced Colorectal Adenoma
Authors: Berndt Sonja I. , Huang Wen-Yi , Fallin M. Daniele , Helzlsouer Kathy J. , Platz Elizabeth A. , Weissfeld Joel L. , Church Timothy R. , Welch Robert , Chanock Stephen J. , Hayes Richard B. 
Published: February 2007

Abstract
Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44–1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64–0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G&gt;A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49–0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% CI, 0.33–0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1, and PARP1 may be associated with advanced colorectal adenoma. [Cancer Res 2007;67(3):1395–404]
p53 Short Peptide (p53pep164) Regulates Lipopolysaccharide-Induced Tumor Necrosis Factor-α Factor/Cytokine Expression
Authors: Tang Xiaoren , Molina Manuel , Amar Salomon 
Published: February 2007

Abstract
The p53 protein is a sequence-specific DNA-binding factor that can induce apoptosis or activate genes whose dysregulation is involved in cancer. By using serial analysis of gene expression technique, p53-induced genes (PIGs) have been identified, one of which was lipopolysaccharide (LPS)–induced tumor necrosis factor-α (TNF-α) factor (LITAF/PIG7). LITAF regulates the transcription of cytokines such as TNF-α. To further elucidate the role of p53 in LITAF expression, LITAF promoter activity was carefully dissected. In this study, we found that the element required for transcriptional activity is mainly located in the region from −990 to −500 of the LITAF promoter; the specific site required for p53 protein-DNA binding is located between −550 and −500. We also found that transient transfection of either a p53 short DNA sequence, called p53LFB12, or its corresponding 7-amino-acid synthetic peptide from amino acids 164 to 170 (K164Q165S166Q167H168M169T170), named p53pep164, significantly reduced LITAF promoter activity to 15% in p53-null H1299 cells. Transfection of p53pep164 into H1299 cells significantly down-regulated LPS-induced LITAF expression as well. Furthermore, transfection of p53pep164 into human monocytes resulted in down-regulation of nine proinflammatory cytokines, including TNF-α. We also found that the LPS-activated p53 is a short-lived protein, and that p53-orchestrated apoptosis occurs shortly after the initiation stage following LPS stimulation and lasts a short time. Once p53 levels return to baseline, the p53-mediated inhibition of LITAF is released, and LITAF-mediated cytokine production can proceed. The present finding proposes a novel link between p53 and the inflammatory processes and highlights potential interventional approaches to control p53-associated inflammatory processes. [Cancer Res 2007;67(3):1308–16]
Prevention of Mantle Lymphoma Tumor Establishment by Routing Transferrin Receptor toward Lysosomal Compartments
Authors: Lepelletier Yves , Camara-Clayette Valérie , Jin Hulin , Hermant Aurélie , Coulon Séverine , Dussiot Michaël , Arcos-Fajardo Michelle , Baude Cédric , Canionni Danielle , Delarue Richard , Brousse Nicole , Benaroch Philippe , Benhamou Marc , Ribrag Vincent , Monteiro Renato C. , Moura Ivan C. , Hermine Olivier 
Published: February 2007

Abstract
Mantle cell lymphoma (MCL) is one of the most frequent of the newly recognized non-Hodgkin's lymphomas. The major problem of MCL therapy is the occurrence of relapse and subsequent resistance to chemotherapy and immunotherapy in virtually all cases. Here, we show that one injection of anti-human transferrin receptor (TfR) monoclonal antibody A24 totally prevented xenografted MCL tumor establishment in nude mice. It also delayed and inhibited tumor progression of established tumors, prolonging mice survival. In vitro, A24 induced up to 85% reduction of MCL cell proliferation (IC50 = 3.75 nmol/L) independently of antibody aggregation, complement-dependent or antibody-dependent cell-mediated cytotoxicity. A24 induced MCL cell apoptosis through caspase-3 and caspase-9 activation, either alone or synergistically with chemotherapeutic agents. A24 induced TfR endocytosis via the clathrin adaptor protein-2 complex pathway followed by transport to lysosomal compartments. Therefore, A24-based therapies alone or in association with classic chemotherapies could provide a new alternative strategy against MCL, particularly in relapsing cases. [Cancer Res 2007;67(3):1145–54]
p53 Enhances Gefitinib-Induced Growth Inhibition and Apoptosis by Regulation of Fas in Non–Small Cell Lung Cancer
Authors: Rho Jin Kyung , Choi Yun Jung , Ryoo Baek-Yeol , Na Im II , Yang Sung Hyun , Kim Cheol Hyeon , Lee Jae Cheol 
Published: February 2007

Abstract
Treatment with gefitinib, a specific inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), has resulted in dramatic responses in some patients with non–small cell lung cancer (NSCLC). Most patients who respond to gefitinib have EGFR-TK mutations; however, &gt;10% of patients with EGFR-TK mutations do not respond. Similarly, some patients without EGFR-TK mutations respond to this drug, suggesting that other factors determine sensitivity to gefitinib. Aberrations of the tumor suppressor gene p53 are frequently associated with drug resistance. In this study, we investigated the role of p53 in growth-inhibitory and apoptotic effects of gefitinib in the human NSCLC cell lines NCI-H1299 and A549, which have no EGFR-TK mutations. NCI-H1299 cells, which had a p53-null genotype, were more resistant to gefitinib compared with A549 cells, which were wild-type p53 (IC50, 40 μmol/L in NCI-H1299 and 5 μmol/L in A549). Treatment of A549 with gefitinib resulted in the translocation of p53 from cytosol to nucleus and the up-regulation of Fas, which was localized to the plasma membrane. In the stable H1299 cell line with tetracycline-inducible p53 expression, induced p53 enhanced growth inhibition and apoptosis by gefitinib through the up-regulation of Fas and restoration of caspase activation. A caspase inhibitor, Z-VAD-fmk, reduced these effects. Conversely, inhibition of p53 using antisense oligonucleotide in A549 caused a significant decrease in apoptosis by gefitinib and down-regulation of Fas under the same conditions. In conclusion, p53 may play a role in determining gefitinib sensitivity by regulating Fas expression in NSCLC. [Cancer Res 2007;67(3):1163–9]
Lapatinib Antitumor Activity Is Not Dependent upon Phosphatase and Tensin Homologue Deleted on Chromosome 10 in ErbB2-Overexpressing Breast Cancers
Authors: Xia Wenle , Husain Intisar , Liu Leihua , Bacus Sarah , Saini Shermini , Spohn Janice , Pry Karen , Westlund Ron , Stein Steven H. , Spector Neil L. 
Published: February 2007

Abstract
Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer. [Cancer Res 2007;67(3):1170–5]
Influence of Bcl-2 Family Members on the Cellular Response of Small-Cell Lung Cancer Cell Lines to ABT-737
Authors: Tahir Stephen K. , Yang Xiufen , Anderson Mark G. , Morgan-Lappe Susan E. , Sarthy Aparna V. , Chen Jun , Warner Robert B. , Ng Shi-Chung , Fesik Stephen W. , Elmore Steve W. , Rosenberg Saul H. , Tse Christin 
Published: February 2007

Abstract
ABT-737 is a novel and potent Bcl-2 antagonist with single-agent activity against small-cell lung cancer (SCLC) cell lines. Here, we evaluated the contribution of Bcl-2 family members to the in vitro cellular response of several SCLC cell lines to ABT-737. Relatively higher levels of Bcl-2, Bcl-XL, Bim and Noxa, and lower levels of Mcl-1 characterized naïve SCLC cell lines that were sensitive to ABT-737. Conversely, a progressive decrease in the relative levels of Bcl-2 and Noxa and a progressive increase in Mcl-1 levels characterized the increased resistance of H146 cells following chronic exposure to ABT-737. Knockdown of Mcl-1 with small interfering RNA sensitized two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitized H196 cells to ABT-737. Combination treatment with DNA-damaging agents was extremely synergistic with ABT-737 and was associated with the down-regulation of Mcl-1 and the up-regulation of Noxa, Puma, and Bim in H196 cells. Thus, SCLC cells sensitive to ABT-737 expressed the target proteins Bcl-2 and Bcl-XL, whereas Mcl-1 and factors regulating Mcl-1 function seem to contribute to the overall resistance of SCLC cells to ABT-737. Overall, these observations provide further insight as to the mechanistic bases for ABT-737 efficacy in SCLC and will be helpful for profiling patients and aiding in the rational design of combination therapies. [Cancer Res 2007;67(3):1176–83]
Colon Cancer Cell–Derived Tumor Necrosis Factor-α Mediates the Tumor Growth–Promoting Response in Macrophages by Up-regulating the Colony-Stimulating Factor-1 Pathway
Authors: Zins Karin , Abraham Dietmar , Sioud Mouldy , Aharinejad Seyedhossein 
Published: February 2007

AbstractThe interplay between malignant and stromal cells is essential in tumorigenesis. We have previously shown that colony-stimulating factor (CSF)-1, matrix metalloprotease (MMP)-2, and vascular endothelial growth factor (VEGF)-A production by stromal cells is enhanced by CSF-1–negative SW620 colon cancer cells. In the present study, the mechanisms by which colon cancer cells up-regulate host factors to promote tumorigenesis were investigated. Profiling of tumor cell cytokine expression in SW620 tumor xenografts in nude mice showed increased human tumor necrosis factor (TNF)-α mRNA expression with tumor growth. Incubation of macrophages with small interfering (si) RNAs directed against TNF-α or TNF-α–depleted SW620 cell conditioned medium versus SW620 cell conditioned medium failed to support mouse macrophage proliferation, migration, and expression of CSF-1, VEGF-A, and MMP-2 mRNAs. Consistent with these results, human TNF-α gene silencing decreased mouse macrophage TNF-α, CSF-1, MMP-2, and VEGF-A mRNA expression in macrophages cocultured with human cancer cells. In addition, inhibition of human TNF-α or mouse CSF-1 expression by siRNA reduced tumor growth in SW620 tumor xenografts in mice. These results suggest that colon cancer cell–derived TNF-α stimulates TNF-α and CSF-1 production by macrophages, and that CSF-1, in turn, induces macrophage VEGF-A and MMP-2 in an autocrine manner. Thus, interrupting tumor cell–macrophage communication by targeting TNF-α may provide an alternative therapeutic approach for the treatment of colon cancer. [Cancer Res 2007;67(3):1038–45]
Ku70 and Poly(ADP-Ribose) Polymerase-1 Competitively Regulate β-Catenin and T-Cell Factor-4–Mediated Gene Transactivation: Possible Linkage of DNA Damage Recognition and Wnt Signaling
Authors: Idogawa Masashi , Masutani Mitsuko , Shitashige Miki , Honda Kazufumi , Tokino Takashi , Shinomura Yasuhisa , Imai Kohzoh , Hirohashi Setsuo , Yamada Tesshi 
Published: February 2007

Abstract
Formation of the T-cell factor-4 (TCF-4) and β-catenin nuclear complex is considered crucial to embryonic development and colorectal carcinogenesis. We previously reported that poly(ADP-ribose) polymerase-1 (PARP-1) interacts with the TCF-4 and β-catenin complex and enhances its transcriptional activity. However, its biological significance remains unexplained. Using immunoprecipitation and mass spectrometry, we found that two Ku proteins, Ku70 and Ku80, were also associated with the complex. Knockdown of Ku70 by RNA interference increased the amount of β-catenin associated with TCF-4 and enhanced the transcriptional activity. PARP-1 competed with Ku70 for binding to TCF-4. Treatment with bleomycin, a DNA-damaging alkylating agent, induced polyADP-ribosylation of PARP-1 protein and inhibited its interaction with TCF-4. Bleomycin conversely increased the amounts of Ku70 coimmunoprecipitated with TCF-4 and removed β-catenin from TCF-4. We propose a working model in which the transcriptional activity of TCF-4 is regulated by the relative amount of Ku70, PARP-1, and β-catenin proteins binding to TCF-4. Identification of the functional interaction of Ku70 as well as PARP-1 with the TCF-4 and β-catenin transcriptional complex may provide insights into a novel linkage between DNA damage recognition/repair and Wnt signaling. [Cancer Res 2007;67(3):911–8]
Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response
Authors: Golding Sarah E. , Rosenberg Elizabeth , Neill Steven , Dent Paul , Povirk Lawrence F. , Valerie Kristoffer 
Published: February 2007

Abstract
The accurate joining of DNA double-strand breaks by homologous recombination repair (HRR) is critical to the long-term survival of the cell. The three major mitogen-activated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH2-kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI–based repair system. First, we verified that this repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an ∼2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not γ-H2AX foci, and suppressed ATM phosphorylation levels &gt;85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ERK pathway is critical for efficient HRR and for radiation-induced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM. [Cancer Res 2007;67(3):1046–53]
Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma
Authors: Du Yong , Honeychurch Jamie , Glennie Martin , Johnson Peter , Illidge Tim 
Published: February 2007

AbstractRadioimmunotherapy is a highly effective treatment for some hematologic malignancies; however, the underlying mechanisms of tumor clearance remain poorly understood. We have previously shown that both targeted radiation using 131I-labeled anti–MHC class II (MHCII) monoclonal antibody (mAb) plus mAb signaling with unlabeled anti-idiotype are required for the long-term clearance of tumor in syngeneic murine lymphoma models. In this study, we have investigated how the microdistribution of the targeted radiation component of this combination affects the long-term clearance of lymphoma. 131I-labeled mAb targeting CD45 and MHCII antigens was found to deliver similar doses of radiation to tumor-bearing organ using conventional dosimetry (∼1.0 Gy per MBq when 131I was labeled to 500 μg mAb and given i.v. per mouse), but when used as radiation vectors in combination therapy only, 131I-anti-MHCII plus anti-idiotype produced long-term survival. The profound differences in therapy did not seem to be dependent on levels of 131I-mAb tumor-binding or antibody-dependent cytotoxicity. Instead, the microscopic intratumoral dosimetry seemed to be critical with the 131I-anti-MHCII, delivering more concentrated and therefore substantially higher radiation dose to tumor cells. When the administered activity of 131I-anti-CD45 was increased, a radiation dose response was shown in the presence of anti-idiotype and long-term survival was seen. We believe that these new insights should influence the selection of new antigen targets and the design of dosimetric methods in radioimmunotherapy of lymphoma. [Cancer Res 2007;67(3):1335–43]