bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth
Authors: Ma Xiaojun , Aoki Tomohiro , Tsuruyama Tatsuaki , Narumiya Shuh
Published: March 2024

Abstract
Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFα and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFα, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFα, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer. Cancer Res; 75(14); 2822–32. ©2015 AACR.
Data from Adaptive Responses to Dasatinib-Treated Lung Squamous Cell Cancer Cells Harboring DDR2 Mutations
Authors: Bai Yun , Kim Jae-Young , Watters January M. , Fang Bin , Kinose Fumi , Song Lanxi , Koomen John M. , Teer Jamie K. , Fisher Kate , Chen Yian Ann , Rix Uwe , Haura Eric B.
Published: March 2024

Abstract
DDR2 mutations occur in approximately 4% of lung squamous cell cancer (SCC) where the tyrosine kinase inhibitor dasatinib has emerged as a new therapeutic option. We found that ERK and AKT phosphorylation was weakly inhibited by dasatinib in DDR2-mutant lung SCC cells, suggesting that dasatinib inhibits survival signals distinct from other oncogenic receptor tyrosine kinases (RTK) and/or compensatory signals exist that dampen dasatinib activity. To gain better insight into dasatinib's action in these cells, we assessed altered global tyrosine phosphorylation (pY) after dasatinib exposure using a mass spectrometry-based quantitative phosphoproteomics approach. Overlaying protein–protein interaction relationships upon this dasatinib-regulated pY network revealed decreased phosphorylation of Src family kinases and their targets. Conversely, dasatinib enhanced tyrosine phosphorylation in a panel of RTK and their signaling adaptor complexes, including EGFR, MET/GAB1, and IGF1R/IRS2, implicating a RTK-driven adaptive response associated with dasatinib. To address the significance of this observation, these results were further integrated with results from a small-molecule chemical library screen. We found that dasatinib combined with MET and insulin-like growth factor receptor (IGF1R) inhibitors had a synergistic effect, and ligand stimulation of EGFR and MET rescued DDR2-mutant lung SCC cells from dasatinib-induced loss of cell viability. Importantly, we observed high levels of tyrosine-phosphorylated EGFR and MET in a panel of human lung SCC tissues harboring DDR2 mutations. Our results highlight potential RTK-driven adaptive-resistant mechanisms upon DDR2 targeting, and they suggest new, rationale cotargeting strategies for DDR2-mutant lung SCC. Cancer Res; 74(24); 7217–28. ©2014 AACR.
Data from Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma
Authors: Faria Claudia C. , Golbourn Brian J. , Dubuc Adrian M. , Remke Marc , Diaz Roberto J. , Agnihotri Sameer , Luck Amanda , Sabha Nesrin , Olsen Samantha , Wu Xiaochong , Garzia Livia , Ramaswamy Vijay , Mack Stephen C. , Wang Xin , Leadley Michael , Reynaud Denis , Ermini Leonardo , Post Martin , Northcott Paul A. , Pfister Stefan M. , Croul Sidney E. , Kool Marcel , Korshunov Andrey , Smith Christian A. , Taylor Michael D. , Rutka James T.
Published: March 2024

Abstract
Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)–driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood–brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma. Cancer Res; 75(1); 134–46. ©2014 AACR.
Data from Effective Cancer Vaccine Platform Based on Attenuated Salmonella and a Type III Secretion System
Authors: Xu Xin , Hegazy Wael A.H. , Guo Linjie , Gao Xiuhua , Courtney Amy N. , Kurbanov Suhrab , Liu Daofeng , Tian Gengwen , Manuel Edwin R. , Diamond Don J. , Hensel Michael , Metelitsa Leonid S.
Published: March 2024

Abstract
Vaccines explored for cancer therapy have been based generally on injectable vector systems used to control foreign infectious pathogens, to which the immune system evolved to respond naturally. However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune system in a manner that is sufficient to engender antitumor responses. We addressed this issue with a novel orally administered Salmonella-based vector that exploits a type III secretion system to deliver selected TAA in the cytosol of professional antigen-presenting cells in situ. A systematic comparison of candidate genes from the Salmonella Pathogenicity Island 2 (SPI2) locus was conducted in the vaccine design, using model antigens and a codon-optimized form of the human TAA survivin (coSVN), an oncoprotein that is overexpressed in most human cancers. In a screen of 20 SPI2 promoter:effector combinations, a PsifB::sseJ combination exhibited maximal potency for antigen translocation into the APC cytosol, presentation to CD8 T cells, and murine immunogenicity. In the CT26 mouse model of colon carcinoma, therapeutic vaccination with a lead PsifB::sseJ-coSVN construct (p8032) produced CXCR3-dependent infiltration of tumors by CD8 T cells, reversed the CD8:Treg ratio at the tumor site, and triggered potent antitumor activity. Vaccine immunogenicity and antitumor potency were enhanced by coadministration of the natural killer T-cell ligand 7DW8-5, which heightened the production of IL12 and IFNγ. Furthermore, combined treatment with p8032 and 7DW8-5 resulted in complete tumor regression in A20 lymphoma-bearing mice, where protective memory was demonstrated. Taken together, our results demonstrate how antigen delivery using an oral Salmonella vector can provide an effective platform for the development of cancer vaccines. Cancer Res; 74(21); 6260–70. ©2014 AACR.
Data from RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway–Dependent Tumors
Authors: Zhao Xuesong , Ponomaryov Tatyana , Ornell Kimberly J. , Zhou Pengcheng , Dabral Sukriti K. , Pak Ekaterina , Li Wei , Atwood Scott X. , Whitson Ramon J. , Chang Anne Lynn S. , Li Jiang , Oro Anthony E. , Chan Jennifer A. , Kelleher Joseph F. , Segal Rosalind A.
Published: March 2024

Abstract
Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy, and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS–MAPK pathway circumvents Shh pathway dependency, drives tumor growth, and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together, these findings reveal a critical role of the RAS–MAPK pathway in drug resistance and tumor evolution of Shh pathway–dependent tumors. Cancer Res; 75(17); 3623–35. ©2015 AACR.
Data from Cytosolic TMEM88 Promotes Invasion and Metastasis in Lung Cancer Cells by Binding DVLS
Authors: Zhang Xiupeng , Yu Xinmiao , Jiang Guiyang , Miao Yuan , Wang Liang , Zhang Yong , Liu Yang , Fan Chuifeng , Lin Xuyong , Dong Qianze , Han Qiang , Zhao Huanyu , Han Yong , Han Xu , Rong Xuezhu , Ding Shuting , Wang Endi , Wang Enhua
Published: March 2024

Abstract
Transmembrane protein 88 (TMEM88) is a transmembrane protein that plays a crucial role in regulating human stem cell differentiation and embryonic development. However, its expression and clinicopathologic significance in human neoplasms is unclear. In this study, the expression and subcellular localizations of TMEM88 were assessed in 214 cases of non–small cell lung cancer (NSCLC). Notably, TMEM88 was highly expressed in the cytosol of ∼60% NSCLC specimens examined. Higher expression of cytosolic TMEM88 in NSCLC correlated significantly with poor differentiation, high TNM stage, lymph node metastasis, and inferior survival. In NSCLC cells displaying membrane-localized TMEM88, we observed an inhibition of canonical Wnt signaling due to interactions of TMEM88 with the Wnt pathway factor Dishevelled (DVLS). In contrast, NSCLC cells with cytosol-localized TMEM88 lacked effects on Wnt signaling. Cytosolic interactions of TMEM88 and DVLS increased the expression of phosphorylated, active forms of p38, GSK3β (Thr390), and Snail, thereby reducing the expression of the tight junction-associated proteins ZO-1 and occludin, effects associated with enhanced invasive and metastatic cell characters. Importantly, attenuating the expression of cytosolic TMEM88 reduced metastatic prowess in xenograft models. Overall, our findings show how mislocalization of TMEM88 to the cytosol in NSCLC cells ablates its Wnt pathway regulatory properties, thereby promoting invasion and metastasis by activating the p38–GSK3β–Snail signaling pathway. Cancer Res; 75(21); 4527–37. ©2015 AACR.
Data from Hepcidin Regulation in Prostate and Its Disruption in Prostate Cancer
Authors: Tesfay Lia , Clausen Kathryn A. , Kim Jin Woo , Hegde Poornima , Wang Xiaohong , Miller Lance D. , Deng Zhiyong , Blanchette Nicole , Arvedson Tara , Miranti Cindy K. , Babitt Jodie L. , Lin Herbert Y. , Peehl Donna M. , Torti Frank M. , Torti Suzy V.
Published: March 2024

Abstract
Hepcidin is a circulating peptide hormone made by the liver that is a central regulator of systemic iron uptake and recycling. Here, we report that prostate epithelial cells also synthesize hepcidin, and that synthesis and secretion of hepcidin are markedly increased in prostate cancer cells and tissue. Prostatic hepcidin functions as an autocrine hormone, decreasing cell surface ferroportin, an iron exporter, increasing intracellular iron retention, and promoting prostate cancer cell survival. Synthesis of hepcidin in prostate cancer is controlled by a unique intersection of pathways that involves BMP4/7, IL6, Wnt, and the dual BMP and Wnt antagonist, SOSTDC1. Epigenetic silencing of SOSTDC1 through methylation is increased in prostate cancer and is associated with accelerated disease progression in patients with prostate cancer. These results establish a new connection between iron metabolism and prostate cancer, and suggest that prostatic dysregulation of hepcidin contributes to prostate cancer growth and progression. Cancer Res; 75(11); 2254–63. ©2015 AACR.
Data from Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
Authors: Mansour Nassir M. , Bernal Giovanna M. , Wu Longtao , Crawley Clayton D. , Cahill Kirk E. , Voce David J. , Balyasnikova Irina V. , Zhang Wei , Spretz Ruben , Nunez Luis , Larsen Gustavo F. , Weichselbaum Ralph R. , Yamini Bakhtiar
Published: March 2024

Abstract
Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB–dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB–binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy. Cancer Res; 75(10); 2039–48. ©2015 AACR.
Data from Naturally Occurring Isothiocyanates Exert Anticancer Effects by Inhibiting Deubiquitinating Enzymes
Authors: Lawson Ann P. , Long Marcus J.C. , Coffey Rory T. , Qian Yu , Weerapana Eranthie , El Oualid Farid , Hedstrom Lizbeth
Published: March 2024

Abstract
The anticancer properties of cruciferous vegetables are well known and attributed to an abundance of isothiocyanates such as benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC). While many potential targets of isothiocyanates have been proposed, a full understanding of the mechanisms underlying their anticancer activity has remained elusive. Here we report that BITC and PEITC effectively inhibit deubiquitinating enzymes (DUB), including the enzymes USP9x and UCH37, which are associated with tumorigenesis, at physiologically relevant concentrations and time scales. USP9x protects the antiapoptotic protein Mcl-1 from degradation, and cells dependent on Mcl-1 were especially sensitive to BITC and PEITC. These isothiocyanates increased Mcl-1 ubiquitination and either isothiocyanate treatment, or RNAi-mediated silencing of USP9x decreased Mcl-1 levels, consistent with the notion that USP9x is a primary target of isothiocyanate activity. These isothiocyanates also increased ubiquitination of the oncogenic fusion protein Bcr-Abl, resulting in degradation under low isothiocyanate concentrations and aggregation under high isothiocyanate concentrations. USP9x inhibition paralleled the decrease in Bcr-Abl levels induced by isothiocyanate treatment, and USP9x silencing was sufficient to decrease Bcr-Abl levels, further suggesting that Bcr-Abl is a USP9x substrate. Overall, our findings suggest that USP9x targeting is critical to the mechanism underpinning the well-established anticancer activity of isothiocyanate. We propose that the isothiocyanate-induced inhibition of DUBs may also explain how isothiocyanates affect inflammatory and DNA repair processes, thus offering a unifying theme in understanding the function and useful application of isothiocyanates to treat cancer as well as a variety of other pathologic conditions. Cancer Res; 75(23); 5130–42. ©2015 AACR.
Data from CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer
Authors: Zhang Qianfei , Qin Jilong , Zhong Lin , Gong Lei , Zhang Bing , Zhang Yan , Gao Wei-Qiang
Published: March 2024

Abstract
The tumor-promoting chemokine CCL5 has been implicated in malignant transformation of breast epithelial cells, with studies to date focusing mainly on basal-type breast cancers. In this study, we investigated the consequences of CCL5 deletion in the MMTV-PyMT transgenic mouse model of luminal breast cancer. In this model, primary tumor burden and pulmonary metastases were reduced significantly in CCL5-deficient subjects, an effect found to be associated with a deficit of Th2 (IL4+CD4+ T) cells. Mechanistic investigations revealed that CCL5 activates CCR3, a highly expressed chemokine receptor on CD4+ T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells, which enhance the prometastatic activity of tumor-associated myeloid cells. Clinically, polarization toward this immunosuppressive Th2 phenotype was also evident in patients with advanced luminal breast cancer. Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4+ T cells, with implications for prognosis and immunotherapy of luminal breast cancer. Cancer Res; 75(20); 4312–21. ©2015 AACR.
Data from A Molecular Portrait of High-Grade Ductal Carcinoma In Situ
Authors: Abba Martin C. , Gong Ting , Lu Yue , Lee Jaeho , Zhong Yi , Lacunza Ezequiel , Butti Matias , Takata Yoko , Gaddis Sally , Shen Jianjun , Estecio Marcos R. , Sahin Aysegul A. , Aldaz C. Marcelo
Published: March 2024

Abstract
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. Cancer Res; 75(18); 3980–90. ©2015 AACR.
Data from Quantifying the Landscape for Development and Cancer from a Core Cancer Stem Cell Circuit
Authors: Li Chunhe , Wang Jin
Published: March 2024

Abstract
Cancer presents a serious threat to human health. The understanding of the cell fate determination during development and tumor-genesis remains challenging in current cancer biology. It was suggested that cancer stem cell (CSC) may arise from normal stem cells or be transformed from normal differentiated cells. This gives hints on the connection between cancer and development. However, the molecular mechanisms of these cell-type transitions and the CSC formation remain elusive. We quantified landscape, dominant paths, and switching rates between cell types from a core gene regulatory network for cancer and development. Stem cell, CSC, cancer, and normal cell types emerge as basins of attraction on associated landscape. The dominant paths quantify the transition processes among CSC, stem cell, normal cell, and cancer cell attractors. Transition actions of the dominant paths are shown to be closely related to switching rates between cell types, but not always to the barriers in between, because of the presence of the curl flux. During the process of P53 gene activation, landscape topography changes gradually from a CSC attractor to a normal cell attractor. This confirms the roles of P53 of preventing the formation of CSC through suppressing self-renewal and inducing differentiation. By global sensitivity analysis according to landscape topography and action, we identified key regulations determining cell-type switchings and suggested testable predictions. From landscape view, the emergence of the CSCs and the associated switching to other cell types are the results of underlying interactions among cancer and developmental marker genes. This indicates that the cancer and development are intimately connected. This landscape and flux theoretical framework provides a quantitative way to understand the underlying mechanisms of CSC formation and interplay between cancer and development. Cancer Res; 75(13); 2607–18. ©2015 AACR.
Data from AKT1 and MYC Induce Distinctive Metabolic Fingerprints in Human Prostate Cancer
Authors: Priolo Carmen , Pyne Saumyadipta , Rose Joshua , Regan Erzsébet Ravasz , Zadra Giorgia , Photopoulos Cornelia , Cacciatore Stefano , Schultz Denise , Scaglia Natalia , McDunn Jonathan , De Marzo Angelo M. , Loda Massimo
Published: March 2024

Abstract
Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor-suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming. Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer. Mass spectrometry–based metabolite profiling was performed on immortalized human prostate epithelial cells transformed by AKT1 or MYC, transgenic mice driven by the same oncogenes under the control of a prostate-specific promoter, and human prostate specimens characterized for the expression and activation of these oncoproteins. Integrative analysis of these metabolomic datasets revealed that AKT1 activation was associated with accumulation of aerobic glycolysis metabolites, whereas MYC overexpression was associated with dysregulated lipid metabolism. Selected metabolites that differentially accumulated in the MYC-high versus AKT1-high tumors, or in normal versus tumor prostate tissue by untargeted metabolomics, were validated using absolute quantitation assays. Importantly, the AKT1/MYC status was independent of Gleason grade and pathologic staging. Our findings show how prostate tumors undergo a metabolic reprogramming that reflects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics. Cancer Res; 74(24); 7198–204. ©2014 AACR.
Data from Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures
Authors: Stone Jennifer , Thompson Deborah J. , dos Santos Silva Isabel , Scott Christopher , Tamimi Rulla M. , Lindstrom Sara , Kraft Peter , Hazra Aditi , Li Jingmei , Eriksson Louise , Czene Kamila , Hall Per , Jensen Matt , Cunningham Julie , Olson Janet E. , Purrington Kristen , Couch Fergus J. , Brown Judith , Leyland Jean , Warren Ruth M.L. , Luben Robert N. , Khaw Kay-Tee , Smith Paula , Wareham Nicholas J. , Jud Sebastian M. , Heusinger Katharina , Beckmann Matthias W. , Douglas Julie A. , Shah Kaanan P. , Chan Heang-Ping , Helvie Mark A. , Le Marchand Loic , Kolonel Laurence N. , Woolcott Christy , Maskarinec Gertraud , Haiman Christopher , Giles Graham G. , Baglietto Laura , Krishnan Kavitha , Southey Melissa C. , Apicella Carmel , Andrulis Irene L. , Knight Julia A. , Ursin Giske , Alnaes Grethe I. Grenaker , Kristensen Vessela N. , Borresen-Dale Anne-Lise , Gram Inger Torhild , Bolla Manjeet K. , Wang Qin , Michailidou Kyriaki , Dennis Joe , Simard Jacques , Pharoah Paul , Dunning Alison M. , Easton Douglas F. , Fasching Peter A. , Pankratz V. Shane , Hopper John L. , Vachon Celine M.
Published: March 2024

Abstract
Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10−5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk. Cancer Res; 75(12); 2457–67. ©2015 AACR.
Data from ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFβ Signaling Pathway
Authors: Li Xiao-Qing , Du Xin , Li Dong-Mei , Kong Peng-Zhou , Sun Yan , Liu Pei-Fang , Wang Qing-Shan , Feng Yu-Mei
Published: March 2024

Abstract
Bone metastasis affects more than 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here, we present clinical and experimental evidence to clarify the role of the integrin β-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence, and growth of cancer cells in bone microenvironment along with osteoclast maturation there to form osteolytic lesions. Mechanistic investigations identified the TGFβ signaling pathway as a downstream effector of ITGBL1 and the transcription factor Runx2 as an upstream activator of ITGBL1 expression. In support of these findings, we also found that ITGBL1 was an essential mediator of Runx2-induced bone metastasis of breast cancer. Overall, our results illuminate how bone metastasis occurs in breast cancer, and they provide functional evidence for new candidate biomarkers and therapeutic targets to identify risk, to prevent, and to treat this dismal feature of advanced breast cancer. Cancer Res; 75(16); 3302–13. ©2015 AACR.
Data from Feed-Forward Reciprocal Activation of PAFR and STAT3 Regulates Epithelial–Mesenchymal Transition in Non–Small Cell Lung Cancer
Authors: Chen Jie , Lan Tian , Zhang Weimin , Dong Lijia , Kang Nan , Zhang Shumin , Fu Ming , Liu Bing , Liu Kangtai , Zhan Qimin
Published: March 2024

Abstract
Platelet-activating factor receptor (PAFR), a G-protein–coupled receptor, has been implicated in tumorigenesis, but its contributions to metastatic progression have not been investigated. Here, we show that PAFR is overexpressed in non–small cell lung cancer (NSCLC) as well as in breast, colorectal, and gastric carcinomas. Expression of PAFR correlates closely with clinical stages, survival time, and distant metastasis. In human NSCLC cells, activation of the PAF/PAFR signaling axis accentuated malignant character, including by stimulating epithelial–mesenchymal transition (EMT). In contrast, silencing PAFR in aggressive NSCLC cells inhibited these effects. Mechanistic investigations showed that PAFR stimulated EMT by activating STAT3 via upregulation of G-protein–dependent SRC or JAK2 kinase activity. Notably, STAT3 transcriptionally elevated PAFR expression. Thus, activation of PAFR in NSCLC cells initiated a forward feedback loop responsible for mediating the aggressive malignant character of NSCLC cells in vitro and in vivo. Reinforcing this reciprocal activation loop, PAF/PAFR signaling also upregulated IL6 expression and thereby STAT3 activation. Overall, our results elucidated an important role for PAFR dysregulation in the pathogenicity of NSCLC and unraveled a forward feedback loop between PAFR and STAT3 that acts to drive the malignant progression of NSCLC. Cancer Res; 75(19); 4198–210. ©2015 AACR.
Data from Vimentin–ERK Signaling Uncouples Slug Gene Regulatory Function
Authors: Virtakoivu Reetta , Mai Anja , Mattila Elina , De Franceschi Nicola , Imanishi Susumu Y. , Corthals Garry , Kaukonen Riina , Saari Markku , Cheng Fang , Torvaldson Elin , Kosma Veli-Matti , Mannermaa Arto , Muharram Ghaffar , Gilles Christine , Eriksson John , Soini Ylermi , Lorens James B. , Ivaska Johanna
Published: March 2024

Abstract
Epithelial–mesenchymal transition (EMT) in cells is a developmental process adopted during tumorigenesis that promotes metastatic capacity. In this study, we advance understanding of EMT control in cancer cells with the description of a novel vimentin–ERK axis that regulates the transcriptional activity of Slug (SNAI2). Vimentin, ERK, and Slug exhibited overlapping subcellular localization in clinical specimens of triple-negative breast carcinoma. RNAi-mediated ablation of these gene products inhibited cancer cell migration and cell invasion through a laminin-rich matrix. Biochemical analyses demonstrated direct interaction of vimentin and ERK, which promoted ERK activation and enhanced vimentin transcription. Consistent with its role as an intermediate filament, vimentin acted as a scaffold to recruit Slug to ERK and promote Slug phosphorylation at serine-87. Site-directed mutagenesis established a requirement for ERK-mediated Slug phosphorylation in EMT initiation. Together, these findings identified a pivotal step in controlling the ability of Slug to organize hallmarks of EMT. Cancer Res; 75(11); 2349–62. ©2015 AACR.
Data from miR-21 Inhibition Reduces Liver Fibrosis and Prevents Tumor Development by Inducing Apoptosis of CD24+ Progenitor Cells
Authors: Zhang Jing , Jiao Jingjing , Cermelli Silvia , Muir Kyle , Jung Kwang Hwa , Zou Ruhai , Rashid Asif , Gagea Mihai , Zabludoff Sonya , Kalluri Raghu , Beretta Laura
Published: March 2024

Abstract
miR-21 is upregulated in hepatocellular carcinoma and intrahepatic cholangiocarcinoma, where it is associated with poor prognosis. Here, we offer preclinical evidence that miR-21 offers a therapeutic and chemopreventive target in these liver cancers. In mice with hepatic deletion of Pten, anti-miR-21 treatment reduced liver tumor growth and prevented tumor development. These effects were accompanied with a decrease in liver fibrosis and a concomitant reduction of CD24+ liver progenitor cells and S100A4+ cancer-associated stromal cells. Notch2 inhibition also occurred in tumors following anti-miR-21 treatment. We further showed that miR-21 is necessary for the survival of CD24+ progenitor cells, a cellular phenotype mediated by Notch2, osteopontin, and integrin αv. Our results identify miR-21 as a key regulator of tumor-initiating cell survival, malignant development, and growth in liver cancer, highlighting the role of CD24+ cells in the expansion of S100A4+ cancer-associated stromal cells and associated liver fibrosis. Cancer Res; 75(9); 1859–67. ©2015 AACR.
Data from A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2
Authors: Yang Shouhui , He Peijun , Wang Jian , Schetter Aaron , Tang Wei , Funamizu Naotake , Yanaga Katsuhiko , Uwagawa Tadashi , Satoskar Abhay R. , Gaedcke Jochen , Bernhardt Markus , Ghadimi B. Michael , Gaida Matthias M. , Bergmann Frank , Werner Jens , Ried Thomas , Hanna Nader , Alexander H. Richard , Hussain S. Perwez
Published: March 2024

Abstract
Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally, and clinically characterized using cell lines, a genetically engineered mouse model, and PDAC patient cohorts. Here, we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b that targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. In addition, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF–mir-301b–NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof of principle for candidate therapies to target a newly described MIF–miR-301b–NR3C2 signaling axis for PDAC management. Cancer Res; 76(13); 3838–50. ©2016 AACR.
Data from Transcriptome Sequencing Reveals PCAT5 as a Novel ERG-Regulated Long Noncoding RNA in Prostate Cancer
Authors: Ylipää Antti , Kivinummi Kati , Kohvakka Annika , Annala Matti , Latonen Leena , Scaravilli Mauro , Kartasalo Kimmo , Leppänen Simo-Pekka , Karakurt Serdar , Seppälä Janne , Yli-Harja Olli , Tammela Teuvo L.J. , Zhang Wei , Visakorpi Tapio , Nykter Matti
Published: March 2024

Abstract
Castration-resistant prostate cancers (CRPC) that arise after the failure of androgen-blocking therapies cause most of the deaths from prostate cancer, intensifying the need to fully understand CRPC pathophysiology. In this study, we characterized the transcriptomic differences between untreated prostate cancer and locally recurrent CRPC. Here, we report the identification of 145 previously unannotated intergenic long noncoding RNA transcripts (lncRNA) or isoforms that are associated with prostate cancer or CRPC. Of the one third of these transcripts that were specific for CRPC, we defined a novel lncRNA termed PCAT5 as a regulatory target for the transcription factor ERG, which is activated in approximately 50% of human prostate cancer. Genome-wide expression analysis of a PCAT5-positive prostate cancer after PCAT5 silencing highlighted alterations in cell proliferation pathways. Strikingly, an in vitro validation of these alterations revealed a complex integrated phenotype affecting cell growth, migration, invasion, colony-forming potential, and apoptosis. Our findings reveal a key molecular determinant of differences between prostate cancer and CRPC at the level of the transcriptome. Furthermore, they establish PCAT5 as a novel oncogenic lncRNA in ERG-positive prostate cancers, with implications for defining CRPC biomarkers and new therapeutic interventions. Cancer Res; 75(19); 4026–31. ©2015 AACR.
Data from Host miR155 Promotes Tumor Growth through a Myeloid-Derived Suppressor Cell–Dependent Mechanism
Authors: Chen Siqi , Wang Long , Fan Jie , Ye Cong , Dominguez Donye , Zhang Yi , Curiel Tyler J. , Fang Deyu , Kuzel Timothy M. , Zhang Bin
Published: March 2024

Abstract
miR155 is a regulator of immune cell development and function that is generally thought to be immunostimulatory. However, we report here that genetic ablation of miR155 renders mice resistant to chemical carcinogenesis and the growth of several transplanted tumors, suggesting that miR155 functions in immunosuppression and tumor promotion. Host miR155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and a reduced ability to license the generation of CD4+Foxp3+ regulatory T cells. Importantly, we demonstrated that miR155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR155 promotes or inhibits tumor growth. Cancer Res; 75(3); 519–31. ©2014 AACR.
Data from Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-κB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer
Authors: Peng Jin , Hamanishi Junzo , Matsumura Noriomi , Abiko Kaoru , Murat Kumuruz , Baba Tsukasa , Yamaguchi Ken , Horikawa Naoki , Hosoe Yuko , Murphy Susan K. , Konishi Ikuo , Mandai Masaki
Published: March 2024

Abstract
Emerging evidence has highlighted the host immune system in modulating the patient response to chemotherapy, but the mechanism of this modulation remains unclear. The aim of this study was to analyze the effect of chemotherapy on antitumor immunity in the tumor microenvironment of ovarian cancer. Treatment of ovarian cancer cell lines with various chemotherapeutic agents resulted in upregulated expression of MHC class I and programmed cell death 1 ligand 1 (PD-L1) in a NF-κB–dependent manner and suppression of antigen-specific T-cell function in vitro. In a mouse model of ovarian cancer, treatment with paclitaxel increased CD8+ T-cell infiltration into the tumor site, upregulated PD-L1 expression, and activated NF-κB signaling. In particular, tumor-bearing mice treated with a combination of paclitaxel and a PD-L1/PD-1 signal blockade survived longer than mice treated with paclitaxel alone. In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF-κB–mediated PD-L1 upregulation. Thus, a combination of chemotherapy and immunotherapy targeting the PD-L1/PD-1 signaling axis may improve the antitumor response and offers a promising new treatment modality against ovarian cancer. Cancer Res; 75(23); 5034–45. ©2015 AACR.
Data from Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity
Authors: Bernardo M. Margarida , Kaplun Alexander , Dzinic Sijana H. , Li Xiaohua , Irish Jonathan , Mujagic Adelina , Jakupovic Benjamin , Back Jessica B. , Van Buren Eric , Han Xiang , Dean Ivory , Chen Yong Q. , Heath Elisabeth , Sakr Wael , Sheng Shijie
Published: March 2024

Abstract
Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of two-dimensional (2D), three-dimensional (3D), and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro, and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro, and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, docetaxel, MS275, and salinomycin were all cytotoxic. In suspension, while MS275 and salinomycin were toxic, docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension and to salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity and enhances tumor sensitivity to salinomycin, which may hold promise in overcoming tumor cell heterogeneity and plasticity. Cancer Res; 75(18); 3970–9. ©2015 AACR.
Data from TLR2 Limits Development of Hepatocellular Carcinoma by Reducing IL18-Mediated Immunosuppression
Authors: Li Shinan , Sun Rui , Chen Yongyan , Wei Haiming , Tian Zhigang
Published: March 2024

Abstract
Immune mechanisms underlying hepatocellular carcinoma (HCC) are not well understood. Here, we show that the Toll-like receptor TLR2 inhibits production of the proinflammatory cytokine IL18 and protects mice from DEN-induced liver carcinogenesis. On this protocol, Tlr2−/− mice exhibited more aggressive HCC development associated with impaired CD8+ T-cell function. Furthermore, Ly6ChighIL18Rα+ myeloid-derived suppressor cells (MDSC) were increased in number in the livers of Tlr2−/− mice before tumor onset. MDSC in this setting exhibited higher iNOS levels that could inhibit IFNγ production and CD8+ T-cell proliferation in vitro. Notably, Tlr2−/− hepatocytes produced more mature IL18 after DEN treatment that was sufficient to drive MDSC accumulation there. IL18 adminstration was sufficient to induce accumulation of MDSC, whereas hepatocyte-specific silencing of IL18 in Tlr2−/− mice decreased the proportion of MDSC, increased the proportion of functional CD8+ T cells, and alleviated HCC progression. IL18 production was mediated by caspase-8 insofar as the decrease in its silencing was sufficient to attenuate levels of mature IL18 in Tlr2−/− mice. Furthermore, the TLR2 agonist Pam3CSK4 inhibited both caspase-8 and IL18 expression, decreasing MDSC, increasing CD8+ T-cell function, and promoting HCC regression. Overall, our findings show how TLR2 deficiency accelerates IL18-mediated immunosuppression during liver carcinogenesis, providing new insights into immune control that may assist the design of effective immunotherapies to treat HCC. Cancer Res; 75(6); 986–95. ©2015 AACR.
Data from Interaction of BARD1 and HP1 Is Required for BRCA1 Retention at Sites of DNA Damage
Authors: Wu Wenwen , Nishikawa Hiroyuki , Fukuda Takayo , Vittal Vinayak , Asano Masahide , Miyoshi Yasuo , Klevit Rachel E. , Ohta Tomohiko
Published: March 2024

Abstract
Stable retention of BRCA1/BARD1 complexes at sites of DNA damage is required for the proper response to DNA double-strand breaks (DSB). Here, we demonstrate that the BRCT domain of BARD1 is crucial for its retention through interaction with HP1. In response to DNA damage, BARD1 interacts with Lys9-dimethylated histone H3 (H3K9me2) in an ATM-dependent but RNF168-independent manner. This interaction is mediated primarily by HP1γ. A conserved HP1-binding motif in the BARD1 BRCT domain directly interacted with the chromoshadow domain of HP1 in vitro. Mutations in this motif (or simultaneous depletion of all three HP1 isoforms) disrupted retention of BARD1, BRCA1, and CtIP at DSB sites and allowed ectopic accumulation of RIF1, an effector of nonhomologous end-joining, at damaged loci in S-phase. UNC0638, a small-molecule inhibitor of histone lysine methyltransferase (HKMT), abolished retention and cooperated with the PARP inhibitor olaparib to block cancer cell growth. Taken together, our findings show how BARD1 promotes retention of the BRCA1/BARD1 complex at damaged DNA sites and suggest the use of HKMT inhibitors to leverage the application of PARP inhibitors to treat breast cancer. Cancer Res; 75(7); 1311–21. ©2015 AACR.
Data from IKKβ Enforces a LIN28B/TCF7L2 Positive Feedback Loop That Promotes Cancer Cell Stemness and Metastasis
Authors: Chen Chong , Cao Fengqi , Bai Lipeng , Liu Yan , Xie Junling , Wang Wei , Si Qin , Yang Jian , Chang Antao , Liu Dong , Liu Dachuan , Chuang Tsung-Hsien , Xiang Rong , Luo Yunping
Published: March 2024

Abstract
Considerable evidence suggests that proinflammatory pathways drive self-renewal of cancer stem-like cells (CSC), but the underlying mechanisms remain mainly undefined. Here we report that the let7 repressor LIN28B and its regulator IKBKB (IKKβ) sustain cancer cell stemness by interacting with the Wnt/TCF7L2 (TCF4) signaling pathway to promote cancer progression. We found that LIN28B expression correlated with clinical progression and stemness marker expression in breast cancer patients. Functional studies demonstrated that the stemness properties of LIN28B-expressing human breast and lung cancer cells were enhanced by IKKβ, whereas loss of LIN28B abolished stemness properties in these settings. These phenomena were driven through interactions with TCF7L2, which enhanced LIN28B expression by direct binding to intron 1 of the LIN28B gene, which in turn promoted TCF7L2 mRNA translation through a positive feedback loop. Notably, RNAi-mediated silencing of LIN28B or pharmacologic inhibition of IKKβ was sufficient to suppress primary and metastatic tumor growth in vivo. Together, our results establish the LIN28B/TCF7L2 interaction loop as a central mediator of cancer stemness driven by proinflammatory processes during progression and metastasis, possibly offering a new therapeutic target for generalized interventions in advanced cancers. Cancer Res; 75(8); 1725–35. ©2015 AACR.