bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of EP4 as a Potential Target for the Treatment of Castration-Resistant Prostate Cancer Using a Novel Xenograft Model
Authors: Terada Naoki , Shimizu Yosuke , Kamba Tomomi , Inoue Takahiro , Maeno Atsushi , Kobayashi Takashi , Nakamura Eijiro , Kamoto Toshiyuki , Kanaji Toshiya , Maruyama Takayuki , Mikami Yoshiki , Toda Yoshinobu , Matsuoka Toshiyuki , Okuno Yasushi , Tsujimoto Gozoh , Narumiya Shuh , Ogawa Osamu 
Published: February 2010

Abstract
More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naïve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. Cancer Res; 70(4); 1606–15
R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer
Authors: Holland Sacha J. , Pan Alison , Franci Christian , Hu Yuanming , Chang Betty , Li Weiqun , Duan Matt , Torneros Allan , Yu Jiaxin , Heckrodt Thilo J. , Zhang Jing , Ding Pingyu , Apatira Ayodele , Chua Joanne , Brandt Ralf , Pine Polly , Goff Dane , Singh Rajinder , Payan Donald G. , Hitoshi Yasumichi 
Published: February 2010

Abstract
Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, &gt;80 days compared with 52 days; P &lt; 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors. Cancer Res; 70(4); 1544–54
miR-181a and miR-630 Regulate Cisplatin-Induced Cancer Cell Death
Authors: Galluzzi Lorenzo , Morselli Eugenia , Vitale Ilio , Kepp Oliver , Senovilla Laura , Criollo Alfredo , Servant Nicolas , Paccard Caroline , Hupé Philippe , Robert Thomas , Ripoche Hugues , Lazar Vladimir , Harel-Bellan Annick , Dessen Philippe , Barillot Emmanuel , Kroemer Guido 
Published: February 2010

Abstract
MicroRNAs (miRNA) are noncoding RNAs that regulate multiple cellular processes, including proliferation and apoptosis. We used microarray technology to identify miRNAs that were upregulated by non–small cell lung cancer (NSCLC) A549 cells in response to cisplatin (CDDP). The corresponding synthetic miRNA precursors (pre-miRNAs) per se were not lethal when transfected into A549 cells yet affected cell death induction by CDDP, C2-ceramide, cadmium, etoposide, and mitoxantrone in an inducer-specific fashion. Whereas synthetic miRNA inhibitors (anti-miRNAs) targeting miR-181a and miR-630 failed to modulate the response of A549 to CDDP, pre-miR-181a and pre-miR-630 enhanced and reduced CDDP-triggered cell death, respectively. Pre-miR-181a and pre-miR-630 consistently modulated mitochondrial/postmitochondrial steps of the intrinsic pathway of apoptosis, including Bax oligomerization, mitochondrial transmembrane potential dissipation, and the proteolytic maturation of caspase-9 and caspase-3. In addition, pre-miR-630 blocked early manifestations of the DNA damage response, including the phosphorylation of the ataxia-telangiectasia mutated (ATM) kinase and of two ATM substrates, histone H2AX and p53. Pharmacologic and genetic inhibition of p53 corroborated the hypothesis that pre-miR-630 (but not pre-miR-181a) blocks the upstream signaling pathways that are ignited by DNA damage and converge on p53 activation. Pre-miR-630 arrested A549 cells in the G0-G1 phase of the cell cycle, correlating with increased levels of the cell cycle inhibitor p27Kip1 as well as with reduced proliferation rates and resulting in greatly diminished sensitivity of A549 cells to the late S-G2-M cell cycle arrest mediated by CDDP. Altogether, these results identify miR-181a and miR-630 as novel modulators of the CDDP response in NSCLC. Cancer Res; 70(5); 1793–803
Reduced Levels of IGF-I Mediate Differential Protection of Normal and Cancer Cells in Response to Fasting and Improve Chemotherapeutic Index
Authors: Lee Changhan , Safdie Fernando M. , Raffaghello Lizzia , Wei Min , Madia Federica , Parrella Edoardo , Hwang David , Cohen Pinchas , Bianchi Giovanna , Longo Valter D. 
Published: February 2010

Abstract
Inhibitors of the insulin-like growth factor-I (IGF-I) receptor have been widely studied for their ability to enhance the killing of a variety of malignant cells, but whether IGF-I signaling differentially protects the host and cancer cells against chemotherapy is unknown. Starvation can protect mice, but not cancer cells, against high-dose chemotherapy [differential stress resistance (DSR)]. Here, we offer evidence that IGF-I reduction mediates part of the starvation-dependent DSR. A 72-hour fast in mice reduced circulating IGF-I by 70% and increased the level of the IGF-I inhibitor IGFBP-1 by 11-fold. LID mice, with a 70% to 80% reduction in circulating IGF-I levels, were protected against three of four chemotherapy drugs tested. Restoration of IGF-I was sufficient to reverse the protective effect of fasting. Sixty percent of melanoma-bearing LID mice treated with doxorubicin achieved long-term survival whereas all control mice died of either metastases or chemotherapy toxicity. Reducing IGF-I/IGF-I signaling protected primary glia, but not glioma cells, against cyclophosphamide and protected mouse embryonic fibroblasts against doxorubicin. Further, S. cerevisiae lacking homologs of IGF-I signaling proteins were protected against chemotherapy-dependent DNA damage in a manner that could be reversed by expressing a constitutively active form of Ras. We conclude that normal cells and mice can be protected against chemotherapy-dependent damage by reducing circulating IGF-I levels and by a mechanism that involves downregulation of proto-oncogene signals. Cancer Res; 70(4); 1564–72
The Bioreductive Prodrug PR-104A Is Activated under Aerobic Conditions by Human Aldo-Keto Reductase 1C3
Authors: Guise Christopher P. , Abbattista Maria R. , Singleton Rachelle S. , Holford Samuel D. , Connolly Joanna , Dachs Gabi U. , Fox Stephen B. , Pollock Robert , Harvey Justin , Guilford Parry , Doñate Fernando , Wilson William R. , Patterson Adam V. 
Published: February 2010

Abstract
PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) family members whose expressions correlated with aerobic metabolism of PR-104A. Plasmid-based expression of candidate genes identified aldo-keto reductase 1C3 as a novel nitroreductase. AKR1C3 protein was detected by Western blot in 7 of 23 cell lines and correlated with oxic PR-104A metabolism, an activity which could be partially suppressed by Nrf2 RNAi knockdown (or induced by Keap1 RNAi), indicating regulation by the ARE pathway. AKR1C3 was unable to sensitize cells to 10 other bioreductive prodrugs and was associated with single-agent PR-104 activity across a panel of 9 human tumor xenograft models. Overexpression in two AKR1C3-negative tumor xenograft models strongly enhanced PR-104 antitumor activity. A population level survey of AKR1C3 expression in 2,490 individual cases across 19 cancer types using tissue microarrays revealed marked upregulation of AKR1C3 in a subset including hepatocellular, bladder, renal, gastric, and non–small cell lung carcinoma. A survey of normal tissue AKR1C3 expression suggests the potential for tumor-selective PR-104A activation by this mechanism. These findings have significant implications for the clinical development of PR-104. Cancer Res; 70(4); 1573–84
DNA Methylation–Dependent Repression of PDZ-LIM Domain–Containing Protein 2 in Colon Cancer and Its Role as a Potential Therapeutic Target
Authors: Qu Zhaoxia , Yan Pengrong , Fu Jing , Jiang Jing , Grusby Michael J. , Smithgall Thomas E. , Xiao Gutian 
Published: February 2010

Abstract
Constitutive activation of the nuclear factor-κB (NF-κB) transcription factor plays a key role in chronic colonic inflammation and colon tumorigenesis. However, the mechanisms by which the tightly regulated NF-κB pathway becomes constitutively activated during colonic pathogenesis remain obscure. Here, we report that PDLIM2, an essential terminator of NF-κB activation, is repressed in various human colorectal cancer cell lines, suggesting one important mechanism for the constitutive activation of NF-κB. Indeed, expression of exogenous PDLIM2 inhibited constitutive NF-κB activation in these colorectal cancer cells. Importantly, the PDLIM2 expression was sufficient to suppress in vitro anchorage-independent growth and in vivo tumor formation of these malignant cells. We have further shown that the PDLIM2 repression involves promoter methylation. Accordingly, treatment of the colorectal tumor cell lines with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine restored PDLIM2 expression and resulted in growth arrest. These studies thus provide new mechanistic insights into colon tumorigenesis by identifying a novel tumor suppressor role for PDLIM2. Cancer Res; 70(5); 1766–72
Antiestrogens Induce Transforming Growth Factor β–Mediated Immunosuppression in Breast Cancer
Authors: Joffroy Christian M. , Buck Miriam B. , Stope Matthias B. , Popp Simone L. , Pfizenmaier Klaus , Knabbe Cornelius 
Published: February 2010

AbstractAntiestrogens are universally used to treat estrogen receptor--positive breast cancer, but relapses occur commonly due to the development of drug resistance. The ability of antiestrogen to induce transforming growth factor β (TGFβ) in breast cancer cells may be relevant to the emergence of resistance, not only at the level of cell autonomous effects of TGFβ on cancer progression but also at the level of its effects on the host immune system. To evaluate the potential role of tumor-derived, antiestrogen-induced TGFβ as an immune suppressor, we established in vitro mixed lymphocyte tumor reactions (MLTR) using MCF-7 cells and peripheral blood mononuclear cells (PBMC), as well as tumor tissue and autologous tumor infiltrating lymphocytes (TIL) obtained from primary breast cancer biopsies. In allogeneic MLTR, antiestrogen-treated MCF-7 cells caused downregulation of the effector molecules granzyme B, perforin, and Fas ligand in CD8+ T cells, and suppressed the generation of cytotoxic effector cells in a TGFβ-dependent manner. Furthermore, we documented induction of regulatory T cells in CD4+ T cells, based on Foxp3 expression and T-cell activation in cocultures. In autologous MLTR, antiestrogen treatment gave rise to enhanced Foxp3 expression of TIL/PBMC and decreased the number of apoptotic tumor cells. These effects were reversed by addition of a TGFβ neutralizing antibody. Our findings offer evidence that antiestrogen induces immunosuppression in the tumor microenvironment, through a TGFβ-dependent mechanism that may contribute to the development of antiestrogen resistance in breast cancer. Cancer Res; 70(4); 1314–22
Sensitivity and Acquired Resistance of BRCA1;p53-Deficient Mouse Mammary Tumors to the Topoisomerase I Inhibitor Topotecan
Authors: Zander Serge A.L. , Kersbergen Ariena , van der Burg Eline , de Water Niels , van Tellingen Olaf , Gunnarsdottir Sjöfn , Jaspers Janneke E. , Pajic Marina , Nygren Anders O.H. , Jonkers Jos , Borst Piet , Rottenberg Sven 
Published: February 2010

AbstractThere is no tailored therapy yet for human basal-like mammary carcinomas. However, BRCA1 dysfunction is frequently present in these malignancies, compromising homology-directed DNA repair. This defect may serve as the tumor's Achilles heel and make the tumor hypersensitive to DNA breaks. We have evaluated this putative synthetic lethality in a genetically engineered mouse model for BRCA1-associated breast cancer, using the topoisomerase I (Top1) poison topotecan as monotherapy and in combination with poly(ADP-ribose) polymerase inhibition by olaparib. All 20 tumors tested were topotecan sensitive, but response heterogeneity was substantial. Although topotecan increased mouse survival, all tumors eventually acquired resistance. As mechanisms of in vivo resistance, we identified overexpression of Abcg2/Bcrp and markedly reduced protein levels of the drug target Top1 (without altered mRNA levels). Tumor-specific genetic ablation of Abcg2 significantly increased overall survival of topotecan-treated animals (P &lt; 0.001), confirming the in vivo relevance of ABCG2 for topotecan resistance in a novel approach. Despite the lack of ABCG2, a putative tumor-initiating cell marker, none of the 11 Abcg2−/−;Brca1−/−;p53−/− tumors were eradicated, not even by the combination topotecan-olaparib. We find that olaparib substantially increases topotecan toxicity in this model, and we suggest that this might also happen in humans. Cancer Res; 70(4); 1700–10
Remote Control of Intestinal Tumorigenesis by Innate Immunity
Authors: Secher Thomas , Gaillot Olivier , Ryffel Bernhard , Chamaillard Mathias 
Published: February 2010

Abstract
Chronic intestinal inflammation has been linked to the development of colorectal cancer. Recent studies suggest that during chronic inflammation, the innate immune system may facilitate colon tumorigenesis in genetically predisposed individuals in response to certain indigenous microorganisms and/or cell remnants. In these individuals, therapeutic approaches that reroute the innate immune system's inflammatory and antimicrobial activities might help prevent colon tumorigenesis and metastasis. Cancer Res; 70(5); 1749–52
General Transcription Factor Binding at CpG Islands in Normal Cells Correlates with Resistance to De novo DNA Methylation in Cancer Cells
Authors: Gebhard Claudia , Benner Chris , Ehrich Mathias , Schwarzfischer Lucia , Schilling Elmar , Klug Maja , Dietmaier Wolfgang , Thiede Christian , Holler Ernst , Andreesen Reinhard , Rehli Michael 
Published: February 2010

Abstract
Aberrant DNA methylation at CpG islands is thought to contribute to cancer initiation and progression, but mechanisms that establish and maintain DNA methylation status during tumorigenesis or normal development remain poorly understood. In this study, we used methyl-CpG immunoprecipitation to generate comparative DNA methylation profiles of healthy and malignant cells (acute leukemia and colorectal carcinoma) for human CpG islands across the genome. While searching for sequence patterns that characterize DNA methylation states, we discovered several nonredundant sequences in CpG islands that were resistant to aberrant de novo methylation in cancer and that resembled consensus binding sites for general transcription factors (TF). Comparing methylation profiles with global CpG island binding data for specific protein 1, nuclear respiratory factor 1, and yin-yang 1 revealed that their DNA binding activity in normal blood cells correlated strictly with an absence of de novo methylation in cancer. In addition, global evidence showed that binding of any of these TFs to their consensus motif depended on their co-occurrence with neighboring consensus motifs. In summary, our results had two major implications. First, they pointed to a major role for cooperative binding of TFs in maintaining the unmethylated status of CpG islands in health and disease. Second, our results suggest that the majority of de novo methylated CpG islands are characterized by the lack of sequence motif combinations and the absence of activating TF binding. Cancer Res; 70(4); 1398–407
Estrogen Suppresses MLK3-Mediated Apoptosis Sensitivity in ER+ Breast Cancer Cells
Authors: Rangasamy Velusamy , Mishra Rajakishore , Mehrotra Suneet , Sondarva Gautam , Ray Rajarshi S. , Rao Arundhati , Chatterjee Malay , Rana Basabi , Rana Ajay 
Published: February 2010

AbstractLittle knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17β-Estradiol (E2) hinders cytotoxic drug–induced cell death in estrogen receptor–positive (ER+) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor–negative (ER−) breast tumors, suggesting that E2 might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH2-terminal kinase, were rapidly inhibited by E2 in ER+ but not in ER− cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E2, indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E2 involved phosphorylation of MLK3 Ser674 by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E2 accentuated this limitation. Taken together, our findings indicate that E2 inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug–induced death of ER+ breast cancer cells. Cancer Res; 70(4); 1731–40
Common Genetic Variants Associated with Breast Cancer and Mammographic Density Measures That Predict Disease
Authors: Odefrey Fabrice , Stone Jennifer , Gurrin Lyle C. , Byrnes Graham B. , Apicella Carmel , Dite Gillian S. , Cawson Jennifer N. , Giles Graham G. , Treloar Susan A. , English Dallas R. , Hopper John L. , Southey Melissa C. ,   for the Australian Twins and Sisters Mammographic Density Study
Published: February 2010

Abstract
Mammographic density for age and body mass index (BMI) is a heritable risk factor for breast cancer. We aimed to determine if recently identified common variants associated with small gradients in breast cancer risk are associated with mammographic density. We genotyped 497 monozygotic and 330 dizygotic twin pairs and 634 of their sisters from 903 families for 12 independent variants. Mammographic dense area, percent dense area, and nondense area were measured by three observers using a computer-thresholding technique. Associations with mammographic density measures adjusted for age, BMI, and other determinants were estimated (a) cross-sectionally using a multivariate normal model for pedigree analysis (Px), (b) between sibships, and (c) within sibships using orthogonal transformations of outcomes and exposures. A combined test of association (Pc) was derived using the independent estimates from b and c. We tested if the distributions of P values across variants differed from the uniform distribution (Pu). For dense area and percent dense area, the distributions of Pc values were not uniform (both Pu &lt;0.007). Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all Px and Pc &lt;0.05), and rs889312 (MAP3K1), rs2107425 (H19), and rs17468277 (CASP8) were marginally associated with dense area (some Px or Pc &lt;0.05). All associations were independent of menopausal status. At least two common breast cancer susceptibility variants are associated with mammographic density measures that predict breast cancer. These findings could help elucidate how those variants and mammographic density measures are associated with breast cancer susceptibility. Cancer Res; 70(4); 1449–58
Interaction of Developmental Transcription Factor HOXC11 with Steroid Receptor Coactivator SRC-1 Mediates Resistance to Endocrine Therapy in Breast Cancer
Authors: McIlroy Marie , McCartan Damian , Early Sarah , Gaora Peadar Ó , Pennington Stephen , Hill Arnold D.K. , Young Leonie S. 
Published: February 2010

Abstract
Mechanisms of acquired resistance to endocrine therapy in breast cancer, a major clinical challenge, are poorly understood. We have used a mass spectrometry–based screen to identify proteins that are associated with the endocrine-resistant phenotype. In this study, we report the identification of a novel pathway of resistance to endocrine therapy involving interactions of the developmental transcription HOXC11 with the steroid receptor coactivator protein SRC-1, which is a strong predictor of reduced disease-free survival in breast cancer patients. HOXC11 and SRC-1 cooperate to regulate expression of the calcium-binding protein S100β in resistant breast cancer cells. Nuclear HOXC11 and S100β were found to strongly predict poor disease-free survival in breast cancer patients (n = 560; hazard ratios: 5.79 and 5.82, respectively; P &lt; 0.0001). Elevated serum levels of S100β detected in patients also predicted reduced disease-free survival (n = 80; hazard ratio: 5.3; P = 0.004). Our findings define a biomolecular interaction network that drives an adaptive response to endocrine therapy with negative consequences for survival in breast cancer. Cancer Res; 70(4); 1585–94