bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Branching Copy-Number Evolution and Parallel Immune Profiles across the Regional Tumor Space of Resected Pancreatic Cancer
Authors: Petersson Alexandra , Andersson Natalie , Hau Sofie Olsson , Eberhard Jakob , Karlsson Jenny , Chattopadhyay Subhayan , Valind Anders , Elebro Jacob , Nodin Björn , Leandersson Karin , Gisselsson David , Jirström Karin
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance is almost inevitable. Herein, we delineated the genetic intratumor heterogeneity in resected PDAC, with the aim to identify evolutionary patterns that may be associated with overall survival (OS) following treatment with curative intent. Potential relationships with the adjacent immune microenvironment were also examined. The genetic and immune landscapes of the regional tumor space were analyzed in nine patients with resected PDAC. Targeted deep sequencing and genome wide SNP array were followed by clonal deconvolution and phylogenetic analysis. A mathematical complexity score was developed to calculate the network extent of each phylogeny. Spatial variation in abundancy and tumor nest infiltration of immune cells was analyzed by double IHC staining. Copy-number heterogeneity was denoted as the major contributing factor to the branching architectures of the produced phylogenetic trees. Increased tree complexity was significantly inversely associated with OS, and larger regional maximum aberrations (higher treetops) were associated with increased PD-L1 expression on tumor cells. Contrastingly, an FREM1 gene amplification, found in one patient, coincided with a particularly vigorous immune response. Findings from this limited case series suggest that complex evolutionary patterns may be associated with a shorter survival in surgically treated patients with PDAC. Some hypothesis-generating associations with the surrounding immune microenvironment were also detected.
Implications:
Evolutionary copy-number patterns may be associated with survival in patients with resected PDAC.
Data from CBX8 Together with SET Facilitates Ovarian Carcinoma Growth and Metastasis by Suppressing the Transcription of SUSD2
Authors: Wu Yanjie , Duan Yang , Li Xuanyuan , Zhao Ran , Lan Bei , Zhang Xingyan , Wang Xiaochen , Chen Hao , Feng Shengyun , Liu Zhenfeng , Cheng Yiming , Xi Lishan , Wang Yingmei , Xue Fengxia , Xuan Chenghao
Published: March 2024

Abstract
Polycomb group proteins are often dysregulated in cancer, leading to disruption of epigenetic landscapes and acquisition of cancer hallmarks. Chromobox 8 (CBX8) is a core component of canonical polycomb repressive complex 1; however, its role in transcriptional regulation and in ovarian carcinoma progression has not been extensively investigated. In this study, we find that CBX8 is upregulated in ovarian cancer. Overexpression and knockdown approaches show that CBX8 facilitates the growth and migration of CAOV3, A2780, and SKOV3 cells in vitro. Consistently, depletion of CBX8 suppresses the growth and metastasis of ovarian carcinoma in vivo. Mechanistically, RNA-sequencing assays together with functional rescue experiments identify a tumor suppressor, SUSD2, as the functional target of CBX8 in ovarian carcinoma cells. Significantly, FLAG affinity coupled with mass spectrometry discovers that CBX8 interacts with a subunit of inhibitor of acetyltransferases (INHAT), SET, which also promotes the growth and migration of A2780 cells. CBX8 and SET cobind to the promoter of SUSD2 to establish H2AK119ub1 and prevent the acetylation of histone H3, resulting in transcriptional suppression of SUSD2.
Implications:
Our study uncovers a novel mechanism CBX8 explores to execute gene repression, and provides new therapeutic targets for ovarian carcinoma.
Data from MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer
Authors: Lee Jia-Ying Lloyd , Ekambaram Prasanna , Carleton Neil M. , Hu Dong , Klei Linda R. , Cai Zongyou , Myers Max I. , Hubel Nathaniel E. , Covic Lidija , Agnihotri Sameer , Krappmann Daniel , Bornancin Frédéric , Lee Adrian V. , Oesterreich Steffi , McAllister-Lucas Linda M. , Lucas Peter C.
Published: March 2024

Abstract
MALT1 is the effector protein of the CARMA/Bcl10/MALT1 (CBM) signalosome, a multiprotein complex that drives pro-inflammatory signaling pathways downstream of a diverse set of receptors. Although CBM activity is best known for its role in immune cells, emerging evidence suggests that it plays a key role in the pathogenesis of solid tumors, where it can be activated by selected G protein–coupled receptors (GPCR). Here, we demonstrated that overexpression of GPCRs implicated in breast cancer pathogenesis, specifically the receptors for Angiotensin II and thrombin (AT1R and PAR1), drove a strong epithelial-to-mesenchymal transition (EMT) program in breast cancer cells that is characteristic of claudin-low, triple-negative breast cancer (TNBC). In concert, MALT1 was activated in these cells and contributed to the dramatic EMT phenotypic changes through regulation of master EMT transcription factors including Snail and ZEB1. Importantly, blocking MALT1 signaling, through either siRNA-mediated depletion of MALT1 protein or pharmacologic inhibition of its activity, was effective at partially reversing the molecular and phenotypic indicators of EMT. Treatment of mice with mepazine, a pharmacologic MALT1 inhibitor, reduced growth of PAR1+, MDA-MB-231 xenografts and had an even more dramatic effect in reducing the burden of metastatic disease. These findings highlight MALT1 as an attractive therapeutic target for claudin-low TNBCs harboring overexpression of one or more selected GPCRs.
Implications:
This study nominates a GPCR/MALT1 signaling axis as a pathway that can be pharmaceutically targeted to abrogate EMT and metastatic progression in TNBC, an aggressive form of breast cancer that currently lacks targeted therapies.
Data from Raptinal Induces Gasdermin E–Dependent Pyroptosis in Naïve and Therapy-Resistant Melanoma
Authors: Vernon Megane , Wilski Nicole A. , Kotas Daniel , Cai Weijia , Pomante Danielle , Tiago Manoela , Alnemri Emad S. , Aplin Andrew E.
Published: March 2024

Abstract
Lack of response and acquired resistance continue to be limitations of targeted and immune-based therapies. Pyroptosis is an inflammatory form of cell death characterized by the release of inflammatory damage-associated molecular patterns (DAMP) and cytokines via gasdermin (GSDM) protein pores in the plasma membrane. Induction of pyroptosis has implications for treatment strategies in both therapy-responsive, as well as resistance forms of melanoma. We show that the caspase-3 activator, raptinal, induces pyroptosis in both human and mouse melanoma cell line models and delays tumor growth in vivo. Release of DAMPs and inflammatory cytokines was dependent on caspase activity and GSDME expression. Furthermore, raptinal stimulated pyroptosis in melanoma models that have acquired resistance to BRAF and MEK inhibitor therapy. These findings add support to efforts to induce pyroptosis in both the treatment-naïve and resistant settings.
Implications:
Raptinal can rapidly induce pyroptosis in naïve and BRAFi plus MEKi-resistant melanoma, which may be beneficial for patients who have developed acquired resistance to targeted therapies.
Data from MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer
Authors: Yamashita Nami , Morimoto Yoshihiro , Fushimi Atsushi , Ahmad Rehan , Bhattacharya Atrayee , Daimon Tatsuaki , Haratake Naoki , Inoue Yuka , Ishikawa Satoshi , Yamamoto Masaaki , Hata Tsuyoshi , Akiyoshi Sayuri , Hu Qiang , Liu Tao , Withers Henry , Liu Song , Shapiro Geoffrey I. , Yoshizumi Tomoharu , Long Mark D. , Kufe Donald
Published: March 2024

Abstract
The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 and IRF1 are essential effectors of type I and II IFN pathways. Here, we report that MUC1-C is necessary for PBRM1 expression and that it forms a nuclear complex with PBRM1 in triple-negative breast cancer (TNBC) cells. Analysis of global transcriptional (RNA-seq) and chromatin accessibility (ATAC-seq) profiles further demonstrated that MUC1-C and PBRM1 drive STAT1 and IRF1 expression by increasing chromatin accessibility of promoter-like signatures (PLS) on their respective genes. We also found that MUC1-C, PBRM1, and IRF1 increase the expression and chromatin accessibility on PLSs of the (i) type II IFN pathway IDO1 and WARS genes and (ii) type I IFN pathway RIG-I, MDA5, and ISG15 genes that collectively contribute to DNA damage resistance and immune evasion. In support of these results, targeting MUC1-C in wild-type BRCA TNBC cells enhanced carboplatin-induced DNA damage and the loss of self-renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal, and tumorigenicity in olaparib-resistant BRCA1-mutant TNBC cells. Analysis of TNBC tumors corroborated that (i) MUC1 and PBRM1 are associated with decreased responsiveness to chemotherapy and (ii) MUC1-C expression is associated with the depletion of tumor-infiltrating lymphocytes (TIL). These findings demonstrate that MUC1-C activates PBRM1, and thereby chromatin remodeling of IFN-stimulated genes that promote chronic inflammation, DNA damage resistance, and immune evasion.
Implications:
MUC1-C is necessary for PBRM1-driven chromatin remodeling in chronic activation of IFN pathway genes that promote DNA damage resistance and immunosuppression.
Data from ATM Regulation of the Cohesin Complex Is Required for Repression of DNA Replication and Transcription in the Vicinity of DNA Double-Strand Breaks
Authors: Bass Thomas E. , Fleenor Donald E. , Burrell Paige E. , Kastan Michael B.
Published: March 2024

Abstract
Ataxia-telangiectasia mutated (ATM) is an apical regulator of responses to DNA double-strand breaks (DSB). Using two complementary unbiased proteomic screens, we identified the cohesin complex proteins PDS5A, PDS5B, RAD21, NIPBL, and WAPL as apparent novel ATM interactors and substrates. ATM-dependent phosphorylation of PDS5A on Ser1278 following treatment with ionizing radiation is required for optimal cell survival, cell-cycle checkpoint activation, and chromosomal stability. Using a system that introduces site-specific DNA breaks, we found that ATM phosphorylation of cohesin proteins SMC1A, SMC3, and PDS5A are all required for repression of both RNA transcription and DNA replication within the vicinity of a DSB, the latter insight based on development of a novel localized S-phase cell-cycle checkpoint assay. These findings highlight the significance of interactions between ATM and cohesin in the regulation of DNA metabolic processes by altering the chromatin environment surrounding a DSB.
Implications:
Multiple members of the cohesin complex are involved in the regulation of DNA replication and transcription in the vicinity of DNA double-strand breaks and their role(s) are regulated by the ATM kinase.
Data from Autocrine Fibronectin Inhibits Breast Cancer Metastasis
Authors: Shinde Aparna , Libring Sarah , Alpsoy Aktan , Abdullah Ammara , Schaber James A. , Solorio Luis , Wendt Michael K.
Published: March 2024

Abstract
Both epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET) are linked to metastasis via their ability to increase invasiveness and enhance tumor-initiating capacity. Growth factors, cytokines, and chemotherapies present in the tumor microenvironment (TME) are capable of inducing EMT, but the role of the extracellular matrix (ECM) in this process remains poorly understood. Here, a novel tessellated three-dimensional (3D) polymer scaffolding is used to produce a fibrillar fibronectin matrix that induces an EMT-like event that includes phosphorylation of STAT3 and requires expression of β1 integrin. Consistent with these findings, analysis of the METABRIC dataset strongly links high-level fibronectin (FN) expression to decreased patient survival. In contrast, in vitro analysis of the MCF-10A progression series indicated that intracellular FN expression was associated with nonmetastatic cells. Therefore, differential bioluminescent imaging was used to track the metastasis of isogenic epithelial and mesenchymal cells within heterogeneous tumors. Interestingly, mesenchymal tumor cells do not produce a FN matrix and cannot complete the metastatic process, even when grown within a tumor containing epithelial cells. However, mesenchymal tumor cells form FN-containing cellular fibrils capable of supporting the growth and migration of metastatic-competent tumor cells. Importantly, depletion of FN allows mesenchymal tumor cells to regain epithelial characteristics and initiate in vivo tumor growth within a metastatic microenvironment.

Implications: In contrast to the tumor-promoting functions of fibronectin within the ECM, these data suggest that autocrine fibronectin production inhibits the metastatic potential of mesenchymal tumor cells. Mol Cancer Res; 16(10); 1579–89. ©2018 AACR.
Data from Cyclin D1 and Cancer Development in Laryngeal Premalignancy Patients
Authors: Papadimitrakopoulou Vassiliki , Izzo Julie G. , Liu Diane D. , Myers Jeffrey , Ceron Tania L. , Lewin Jan , William William N. , Atwell Anthea , Lee J. Jack , Gillenwater Ann , El-Naggar Adel , Wu Xifeng , Lippman Scott M. , Hittelman Walter N. , Hong Waun Ki
Published: March 2024

Abstract
In a previous trial, we found that combined 13-cis-retinoic acid, IFN-α, and α-tocopherol more effectively reversed advanced premalignant lesions of the larynx than of the oral cavity and that cyclin D1 (CD1) G/A870 single nucleotide polymorphism correlated with cancer risk. We conducted the present trial primarily to confirm the clinical activity of the combination in advanced laryngeal premalignancy and to confirm and extend our findings on CD1, both genotype and protein expression, in association with cancer risk in this setting. Twenty-seven moderate-to-severe laryngeal dysplasia patients underwent induction with combined 13-cis-retinoic acid daily, α-IFN twice weekly, and α-tocopherol daily for 1 year; 14 nonprogressing patients then were randomized to maintenance fenretinide or placebo for 2 years. During induction, two patients had pathologic complete responses, six had partial responses (30% overall response rate), and five developed laryngeal cancer. There were no significant differences between maintenance fenretinide and placebo in response or cancer rates. Ten patients developed cancer overall. Twenty-four patients were evaluated for the CD1 G/A870 genotype, and 23 for pretreatment and posttreatment CD1 protein expression. Consistent with our earlier report, shorter cancer-free survival was associated with the CD1 AA/AG genotype (P = 0.05). Extending our earlier work, high CD1 expression was associated with worse cancer-free survival overall (P = 0.04) and within each CD1 genotype group. These findings support CD1 genotype and protein expression as important risk markers for laryngeal cancer and suggest future trials targeting upstream regulators of CD1 transcription.
Data from Objective Detection and Delineation of Oral Neoplasia Using Autofluorescence Imaging
Authors: Roblyer Darren , Kurachi Cristina , Stepanek Vanda , Williams Michelle D. , El-Naggar Adel K. , Lee J. Jack , Gillenwater Ann M. , Richards-Kortum Rebecca
Published: March 2024

Abstract
Although the oral cavity is easily accessible to inspection, patients with oral cancer most often present at a late stage, leading to high morbidity and mortality. Autofluorescence imaging has emerged as a promising technology to aid clinicians in screening for oral neoplasia and as an aid to resection, but current approaches rely on subjective interpretation. We present a new method to objectively delineate neoplastic oral mucosa using autofluorescence imaging.

Autofluorescence images were obtained from 56 patients with oral lesions and 11 normal volunteers. From these images, 276 measurements from 159 unique regions of interest (ROI) sites corresponding to normal and confirmed neoplastic areas were identified. Data from ROIs in the first 46 subjects were used to develop a simple classification algorithm based on the ratio of red-to-green fluorescence; performance of this algorithm was then validated using data from the ROIs in the last 21 subjects. This algorithm was applied to patient images to create visual disease probability maps across the field of view. Histologic sections of resected tissue were used to validate the disease probability maps.

The best discrimination between neoplastic and nonneoplastic areas was obtained at 405 nm excitation; normal tissue could be discriminated from dysplasia and invasive cancer with a 95.9% sensitivity and 96.2% specificity in the training set, and with a 100% sensitivity and 91.4% specificity in the validation set. Disease probability maps qualitatively agreed with both clinical impression and histology. Autofluorescence imaging coupled with objective image analysis provided a sensitive and noninvasive tool for the detection of oral neoplasia.
Data from Oropharyngeal Cancer, Race, and the Human Papillomavirus
Authors: Brawley Otis W.
Published: March 2024

Abstract
This perspective on Settle et al. (beginning on p. 776 in this issue of the journal) discusses the racial disparity in oropharyngeal cancer survival in relation to the biological factor human papillomavirus and its association with sexual behavior. This discussion is expanded to a more general consideration of biological and nonbiological (e.g., socioeconomic and cultural) factors affecting racial disparities in disease.
Data from Is It Time to Advance the Chemoprevention of Environmental Carcinogenesis with Microdosing Trials?
Authors: Kensler Thomas W. , Groopman John D.
Published: March 2024

Abstract
This perspective on Jubert et al. (beginning on page [1015] in this issue of the journal) discusses the use of microdosing with environmental carcinogens to accelerate the evaluation and optimization of chemopreventive interventions. The need for chemoprevention of environmental carcinogenesis is considered, as are the structure of microdosing, or phase 0, trials, technologies required to conduct microdose studies in this context, and ethical concerns. We also reflect on what microdosing studies have taught us to date.
Data from Walking the Walk from Genes through Telomere Maintenance to Cancer Risk
Authors: Blackburn Elizabeth H.
Published: March 2024

Abstract
Recent studies have shown associations between human population single-nucleotide polymorphisms (SNP) and white blood cell telomere shortness; independently, telomere shortness has been associated with higher risks of various cancers. However, no single previous study simultaneously linked a given SNP both with telomere length and reduced risk of cancer. In this issue of the journal (beginning on page 514), Gu and colleagues report four new SNPs associated, in three cohorts, with telomere length. One of these SNPs predicted risk for bladder cancer, an effect partially mediated by telomere length. Interventions that could forestall telomere shortening should be explored for their potential to reduce cancer risks. Cancer Prev Res; 4(4); 473–5. ©2011 AACR.
Data from Increased Levels of Urinary PGE-M, a Biomarker of Inflammation, Occur in Association with Obesity, Aging, and Lung Metastases in Patients with Breast Cancer
Authors: Morris Patrick G. , Zhou Xi Kathy , Milne Ginger L. , Goldstein Daniel , Hawks Laura C. , Dang Chau T. , Modi Shanu , Fornier Monica N. , Hudis Clifford A. , Dannenberg Andrew J.
Published: March 2024

Abstract
Elevated levels of COX-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n = 200), lung metastases (n = 100), and metastases to other sites (n = 100). Patients completed a questionnaire, provided urine, and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) had the highest PGE-M levels. PGE-M levels were increased in association with elevated body mass index (BMI; P < 0.001), aging (P < 0.001), pack-year smoking history (P = 0.02), lung metastases (P = 0.02), and recent cytotoxic chemotherapy (P = 0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (P < 0.001). On the basis of the current findings, PGE-M is likely to be a useful biomarker for the selection of high-risk subgroups to determine the use of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women. Cancer Prev Res; 6(5); 428–36. ©2013 AACR.
Data from The Synthetic Triterpenoid CDDO-Methyl Ester Delays Estrogen Receptor–Negative Mammary Carcinogenesis in Polyoma Middle T Mice
Authors: Tran Kim , Risingsong Renee , Royce Darlene , Williams Charlotte R. , Sporn Michael B. , Liby Karen
Published: March 2024

Abstract
Novel drugs are needed for the prevention and treatment of breast cancer. Synthetic triterpenoids are a promising new class of compounds with activity in a variety of preclinical cancer models. We tested activity of the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of estrogen receptor–negative breast cancer, the polyoma-middle T (PyMT), in which the oncoprotein drives carcinogenesis. The developing tumors recapitulate key features of the human disease. Mice were fed CDDO-Me (50 mg/kg diet), starting at 4 weeks of age. CDDO-Me significantly increased the age of mice at onset of first tumor (P < 0.001) by an average of 4.3 weeks and overall survival (P < 0.001) by 5.2 weeks. The drug also inhibited the infiltration of tumor-associated macrophages into mammary glands of PyMT mice at 12 weeks of age and reduced levels of the chemokines CXCL12 and CCL2 in primary PyMT mammary tumor cells. Treatment with this multifunctional drug also inhibited secretion of matrix metalloproteinase-9 in primary tumor cells from PyMT mice and decreased proliferation of these cells by inhibiting cyclin D1 and decreasing phosphorylation of epidermal growth factor receptor and STAT3. Cancer Prev Res; 5(5); 726–34. ©2012 AACR.
Data from Induction of Retinoid X Receptor Activity and Consequent Upregulation of p21WAF1/CIP1 by Indenoisoquinolines in MCF7 Cells
Authors: Park Eun-Jung , Kondratyuk Tamara P. , Morrell Andrew , Kiselev Evgeny , Conda-Sheridan Martin , Cushman Mark , Ahn Soyoun , Choi Yongsoo , White Jerry J. , van Breemen Richard B. , Pezzuto John M.
Published: March 2024

Abstract
Retinoid X receptor (RXR) has been targeted for the chemoprevention and treatment of cancer. To discover potential agents acting through RXRs, we utilized an RXR response element (RXRE)-luciferase reporter gene assay. Following extensive screening, 3-amino-6-(3-aminopropyl)-5,6-dihydro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline dihydrochloride (AM6-36) was found to induce RXRE-luciferase activities. AM6-36 inhibited COX-2 expression and anchorage-independent growth with 12-O-tetradecanoylphorbol 13-acetate-stimulated JB6 Cl41 cells, induced the expression of CD38 in HL-60 cells, and attenuated the growth of N-methyl-N-nitrosourea–induced mammary tumors in rats. Consistent with other reports describing the antiproliferative effects of RXR agonists in breast cancers, AM6-36 showed growth inhibition with cultured MCF7 breast cancer cells, accompanied by G2/M-phase arrest at lower concentrations and enhanced S-phase arrest at higher concentrations. On the basis of DNA microarray analysis, AM6-36 upregulated the expression of CDKN1A, a target gene of RXR, by 35-fold. In accord with this response, the expression of the corresponding protein, p21WAF1/CIP1, was increased in the presence of AM6-36. Induction of p21 by AM6-36 was abrogated following transient knockdown of RXRα, demonstrating that the effect of AM6-36 on the expression of p21 is closely related to modulation of RXRα transcriptional activity. Intestinal permeability was suggested with Caco-2 cells and limited metabolism resulted when AM6-36 was incubated with human liver microsomes. Oral administration with rats resulted in 0.8 μg/mL, 4.3 μg/g, and 0.3 μg/g in serum, liver, and mammary gland, respectively. In sum, these data suggest that AM6-36 is a promising lead for the treatment or prevention of breast cancer and provide a strong rationale for testing in more advanced antitumor systems. Cancer Prev Res; 4(4); 592–607. ©2011 AACR.
Data from Deguelin Inhibits Growth of Breast Cancer Cells by Modulating the Expression of Key Members of the Wnt Signaling Pathway
Authors: Murillo Genoveva , Peng Xinjian , Torres Karen E.O. , Mehta Rajendra G.
Published: March 2024

Abstract
An emphasis in early detection and more effective treatments has decreased the mortality rate of breast cancer. Despite this decrease, breast cancer continues to be the leading cause of death among women between 40 and 55 years of age and is the second overall cause of death among women. Hence, the aim of the present study was to assess the therapeutic efficacy of deguelin, a rotenoid isolated from several plant species, which has been reported to have chemopreventive and/or chemotherapeutic effects in skin, mammary, colon, and lung cancers. The effect of deguelin on cell proliferation was evaluated using four human breast carcinoma cell lines (MCF-7, BT474, T47D, and MDA-MB-231) by cell count and MTT. Moreover, apoptosis was evaluated by acridine/ethidium staining and DNA laddering. Gene expression changes following deguelin treatment in MDA-MB-231 cells was assessed through microarray analysis. Deguelin at 1 μmol/L was found to inhibit the growth of the breast cancer cell lines tested with a range of 37% to 87%. The highest inhibition was noted for the MDA-MB-231 cell line (MDA-MB-231>BT474>MCF7>T47D>MCF12F). An arrest at the S phase of the cell cycle and apoptosis were shown in the MDA-MB-231 cells treated with deguelin. The microarray profile indicated differential expression of two independent pathways, including clusters of apoptosis and Wnt/β-catenin signaling genes in cells as a result of deguelin treatment. These studies support the antiproliferative effects of deguelin in human breast cancer cells and, perhaps more importantly, illustrate novel actions by deguelin in the Wnt signaling pathway.
Data from Allelic Transcripts Dosage Effect in Morphologically Normal Ovarian Cells from Heterozygous Carriers of a BRCA1/2 French Canadian Founder Mutation
Authors: Abd-Rabbo Diala , Abaji Christine , Cardin Guillaume B. , Filali-Mouhim Abdelali , Arous Caroline , Portelance Lise , Escobar Enrique , Cloutier Sophie , Tonin Patricia N. , Provencher Diane M. , Mes-Masson Anne-Marie , Maugard Christine M.
Published: March 2024

Abstract
We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated with ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from BRCA2-8765delAG carriers. Further analysis of morphologically normal ovarian and tumor cells from BRCA1-4446C>T carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cells. The highest level of BRCA2-mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript. Cancer Prev Res; 5(5); 765–77. ©2012 AACR.
Data from Regulation of Prostaglandin Transporters in Colorectal Neoplasia
Authors: Holla Vijaykumar R. , Backlund Michael G. , Yang Peying , Newman Robert A. , DuBois Raymond N.
Published: March 2024

Abstract
Prostaglandin E2 (PGE2) promotes cancer progression by affecting cell proliferation, apoptosis, angiogenesis, and the immune response. It has been reported that PGE2 is transported or passes through the cell membrane via prostaglandin-specific transporters including the prostaglandin transporter (PGT, an influx transporter) and the multidrug resistance-associated protein 4 (an efflux transporter). PGT can facilitate the removal of PGE2 from the extracellular milieu by transporting it into the cell, where 15-hydroxyprostaglandin dehydrogenase (15-PGDH) then oxidizes PGE2 into 15-keto PGE2. We previously reported that 15-PGDH expression is reduced in most colorectal cancers, indicating the tumor suppressor role of this gene. In the present study, we show that PGT expression is also decreased (whereas multidrug resistance-associated protein 4 expression is elevated) in human colorectal cancer specimens (compared with expression in normal mucosa) and in colorectal cancer cell lines. Furthermore, we found that PGT expression decreased in premalignant adenomas in APCmin mice and was partially restored (in human colorectal cancer cell lines) by treatment with a DNA demethylating agent or histone deacetylase inhibitor. Forced PGT overexpression in vitro dose dependently reduced extracellular PGE2 levels and increased intracellular levels of its catabolic product 15-keto PGE2. Our collective data suggest that the existing model to explain increased PGE2 in colorectal neoplasia should be modified to include the novel mechanism of coordinated up- and down-regulation of genes involved in PGE2 transport.
Data from Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia
Authors: Gümüş Zeynep H. , Du Baoheng , Kacker Ashutosh , Boyle Jay O. , Bocker Jennifer M. , Mukherjee Piali , Subbaramaiah Kotha , Dannenberg Andrew J. , Weinstein Harel
Published: March 2024

Abstract
In addition to being causally linked to the formation of multiple tumor types, tobacco use has been associated with decreased efficacy of anticancer treatment and reduced survival time. A detailed understanding of the cellular mechanisms that are affected by tobacco smoke (TS) should facilitate the development of improved preventive and therapeutic strategies. We have investigated the effects of a TS extract on the transcriptome of MSK-Leuk1 cells, a cellular model of oral leukoplakia. Using Affymetrix HGU133 Plus 2 arrays, 411 differentially expressed probe sets were identified. The observed transcriptome changes were grouped according to functional information and translated into molecular interaction network maps and signaling pathways. Pathways related to cellular proliferation, inflammation, apoptosis, and tissue injury seemed to be perturbed. Analysis of networks connecting the affected genes identified specific modulated molecular interactions, hubs, and key transcription regulators. Thus, TS was found to induce several epidermal growth factor receptor (EGFR) ligands forming an EGFR-centered molecular interaction network, as well as several aryl hydrocarbon receptor–dependent genes, including the xenobiotic metabolizing enzymes CYP1A1 and CYP1B1. Notably, the latter findings in vitro are consistent with our parallel finding that CYP1A1 and CYP1B1 levels were increased in oral mucosa of smokers. Collectively, these results offer insights into the mechanisms underlying the procarcinogenic effects of TS and raise the possibility that inhibitors of EGFR or aryl hydrocarbon receptor signaling will prevent or delay the development of TS-related tumors. Moreover, the inductive effects of TS on xenobiotic metabolizing enzymes may help explain the reduced efficacy of chemotherapy, and suggest targets for chemopreventive agents in smokers.
Data from Isolating the Effects of Social Interactions on Cancer Biology
Authors: Trainor Brian C. , Sweeney Colleen , Cardiff Robert
Published: March 2024

Abstract
This perspective on Williams et al. (beginning on p. 850 in this issue of the journal) examines the connections between biological responses activated during psychosocial stress and mammary tumorigenesis. Experiments in mouse models of cancer are identifying aspects of tumor biology that may be regulated by hormones such as glucocorticoids released during psychosocial stress. Our growing understanding of the actions of glucocorticoids on breast tumors could lead to important changes in cancer treatment.
Data from Chromoendoscopy Detects More Adenomas than Colonoscopy Using Intensive Inspection without Dye Spraying
Authors: Stoffel Elena M. , Turgeon D. Kim , Stockwell David H. , Normolle Daniel P. , Tuck Missy K. , Marcon Norman E. , Baron John A. , Bresalier Robert S. , Arber Nadir , Ruffin Mack T. , Syngal Sapna , Brenner Dean E.
Published: March 2024

Abstract
Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy.

Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded.

Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 ± 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone.

Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.
Data from Tumor Suppressor microRNAs, miR-100 and -125b, Are Regulated by 1,25-dihydroxyvitamin D in Primary Prostate Cells and in Patient Tissue
Authors: Giangreco Angeline A. , Vaishnav Avani , Wagner Dennis , Finelli Antonio , Fleshner Neil , Van der Kwast Theodorus , Vieth Reinhold , Nonn Larisa
Published: March 2024

Abstract
MiR-100 and miR-125b are lost in many cancers and have potential function as tumor suppressors. Using both primary prostatic epithelial cultures and laser capture-microdissected prostate epithelium from 45 patients enrolled in a vitamin D3 randomized trial, we identified miR-100 and -125b as targets of 1,25-dihydroxyvitamin D3 (1,25D). In patients, miR-100 and -125b levels were significantly lower in tumor tissue than in benign prostate. Similarly, miR-100 and -125b were lower in primary prostate cancer cells than in cells derived from benign prostate. Prostatic concentrations of 1,25D positively correlated with these miRNA levels in both prostate cancer and benign epithelium, showing that patients with prostate cancer may still benefit from vitamin D3. In cell assays, upregulation of these miRNAs by 1,25D was vitamin D receptor dependent. Transfection of pre-miR-100 and pre-miR-125b in the presence or absence of 1,25D decreased invasiveness of cancer cell, RWPE-2. Pre-miR-100 and pre-miR-125b decreased proliferation in primary cells and cancer cells respectively. Pre-miR-125b transfection suppressed migration and clonal growth of prostate cancer cells, whereas knockdown of miR-125b in normal cells increased migration indicates a tumor suppressor function. 1,25D suppressed expression of previously bona fide mRNA targets of these miRNAs, E2F3 and Plk1, in a miRNA-dependent manner. Together, these findings show that vitamin D3 supplementation augments tumor suppressive miRNAs in patient prostate tissue, providing evidence that miRNAs could be key physiologic mediators of vitamin D3 activity in prevention and early treatment of prostate cancer. Cancer Prev Res; 6(5); 483–94. ©2013 AACR.
Data from Knockout of the Tumor Suppressor Gene Gprc5a in Mice Leads to NF-κB Activation in Airway Epithelium and Promotes Lung Inflammation and Tumorigenesis
Authors: Deng Jiong , Fujimoto Junya , Ye Xiao-Feng , Men Tao-Yan , Van Pelt Carolyn S. , Chen Yu-Long , Lin Xiao-Feng , Kadara Humam , Tao Qingguo , Lotan Dafna , Lotan Reuben
Published: March 2024

Abstract
Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents. We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a. Examination of normal lung tissue and tumors from 51 Gprc5a+/+ (adenoma incidence, 9.8%; adenocarcinoma, 0%) and 38 Gprc5a−/− mice (adenoma, 63%; adenocarcinoma, 21%) revealed macrophage infiltration into lungs of 45% of the Gprc5a−/− mice and 8% of Gprc5a+/+ mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice. Gprc5a−/− mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a+/+ mice to stimulation of NF-κB activation by lipopolysaccharide in vivo. Studies with epithelial cells cultured from tracheas of Gprc5a−/− and Gprc5a+/+ mice revealed that Gprc5a loss is associated with increased cell proliferation, resistance to cell death in suspension, and increased basal, tumor necrosis factor α–induced, and lipopolysaccharide-induced NF-κB activation, which were reversed partially in Gprc5a−/− adenocarcinoma cells by reexpression of Gprc5a. Compared with Gprc5a+/+ cells, the Gprc5a−/− cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration. Silencing Gprc5a and the p65 subunit of NF-κB in Gprc5a+/+ and Gprc5a−/− cells, respectively, reversed these effects. Thus, Gprc5a loss enhances NF-κB activation in lung epithelial cells, leading to increased autocrine and paracrine interactions, cell autonomy, and enhanced inflammation, which may synergize in the creation of a tumor-promoting microenvironment. Cancer Prev Res; 3(4); 424–37. ©2010 AACR.
Data from The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6
Authors: Toyokawa Gouji , Cho Hyun-Soo , Iwai Yukiko , Yoshimatsu Masanori , Takawa Masashi , Hayami Shinya , Maejima Kazuhiro , Shimizu Noriaki , Tanaka Hirotoshi , Tsunoda Tatsuhiko , Field Helen I. , Kelly John D. , Neal David E. , Ponder Bruce A.J. , Maehara Yoshihiko , Nakamura Yusuke , Hamamoto Ryuji
Published: March 2024

Abstract
Histone methyltransferases and demethylases are known to regulate transcription by altering the epigenetic marks on histones, but the pathologic roles of their dysfunction in human diseases, such as cancer, still remain to be elucidated. Herein, we show that the histone demethylase JMJD2B is involved in human carcinogenesis. Quantitative real-time PCR showed notably elevated levels of JMJD2B expression in bladder cancers, compared with corresponding nonneoplastic tissues (P < 0.0001), and elevated protein expression was confirmed by immunohistochemistry. In addition, cDNA microarray analysis revealed transactivation of JMJD2B in lung cancer, and immunohistochemical analysis showed protein overexpression in lung cancer. siRNA-mediated reduction of expression of JMJD2B in bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells, and suppressing JMJD2B expression lead to a decreased population of cancer cells in S phase, with a concomitant increase of cells in G1 phase. Furthermore, a clonogenicity assay showed that the demethylase activity of JMJD2B possesses an oncogenic activity. Microarray analysis after knockdown of JMJD2B revealed that JMJD2B could regulate multiple pathways which contribute to carcinogenesis, including the cell-cycle pathway. Of the downstream genes, chromatin immunoprecipitation showed that CDK6 (cyclin-dependent kinase 6), essential in G1–S transition, was directly regulated by JMJD2B, via demethylation of histone H3-K9 in its promoter region. Expression levels of JMJD2B and CDK6 were significantly correlated in various types of cell lines. Deregulation of histone demethylation resulting in perturbation of the cell cycle, represents a novel mechanism for human carcinogenesis and JMJD2B is a feasible molecular target for anticancer therapy. Cancer Prev Res; 4(12); 2051–61. ©2011 AACR.
Data from DNA Methylation of Phosphatase and Actin Regulator 3 Detects Colorectal Cancer in Stool and Complements FIT
Authors: Bosch Linda J.W. , Oort Frank A. , Neerincx Maarten , Khalid-de Bakker Carolina A.J. , sive Droste Jochim S. Terhaar , Melotte Veerle , Jonkers Daisy M.A.E. , Masclee Ad A.M. , Mongera Sandra , Grooteclaes Madeleine , Louwagie Joost , van Criekinge Wim , Coupé Veerle M.H. , Mulder Chris J. , van Engeland Manon , Carvalho Beatriz , Meijer Gerrit A.
Published: March 2024

Abstract
Using a bioinformatics-based strategy, we set out to identify hypermethylated genes that could serve as biomarkers for early detection of colorectal cancer (CRC) in stool. In addition, the complementary value to a Fecal Immunochemical Test (FIT) was evaluated. Candidate genes were selected by applying cluster alignment and computational analysis of promoter regions to microarray-expression data of colorectal adenomas and carcinomas. DNA methylation was measured by quantitative methylation-specific PCR on 34 normal colon mucosa, 71 advanced adenoma, and 64 CRC tissues. The performance as biomarker was tested in whole stool samples from in total 193 subjects, including 19 with advanced adenoma and 66 with CRC. For a large proportion of these series, methylation data for GATA4 and OSMR were available for comparison. The complementary value to FIT was measured in stool subsamples from 92 subjects including 44 with advanced adenoma or CRC. Phosphatase and Actin Regulator 3 (PHACTR3) was identified as a novel hypermethylated gene showing more than 70-fold increased DNA methylation levels in advanced neoplasia compared with normal colon mucosa. In a stool training set, PHACTR3 methylation showed a sensitivity of 55% (95% CI: 33–75) for CRC and a specificity of 95% (95% CI: 87–98). In a stool validation set, sensitivity reached 66% (95% CI: 50–79) for CRC and 32% (95% CI: 14–57) for advanced adenomas at a specificity of 100% (95% CI: 86–100). Adding PHACTR3 methylation to FIT increased sensitivity for CRC up to 15%. PHACTR3 is a new hypermethylated gene in CRC with a good performance in stool DNA testing and has complementary value to FIT. Cancer Prev Res; 5(3); 464–72. ©2011 AACR.
Data from N-nitroso-tris-chloroethylurea Induces Premalignant Squamous Dysplasia in Mice
Authors: Hudish Tyler M. , Opincariu Laura I. , Mozer Anthony B. , Johnson Micah S. , Cleaver Timothy G. , Malkoski Stephen P. , Merrick Daniel T. , Keith Robert L.
Published: March 2024

Abstract
Squamous cell carcinoma (SCC) and premalignant endobronchial lesions have been difficult to study in murine models. In this study, we evaluate the topical N-nitroso-tris-chloroethylurea (NTCU) murine SCC model, determine the extent to which resulting premalignant airway dysplasia develops, discuss clinicopathologic grading criteria in lesion progression, and confirm that immunohistochemical (IHC) staining patterns are consistent with those observed in human endobronchial dysplasia and SCC. Male and female FVB mice were treated biweekly with topical NTCU (4, 8, or 40 mmol/L) or vehicle for 32 weeks. Following sacrifice, squamous cell lesions were enumerated and categorized into the following groups: flat atypia, low-grade dysplasia, high-grade dysplasia, and invasive SCC. The 40 mmol/L NTCU concentration produced the entire spectrum of premalignant dysplasias and squamous cell carcinomas, but was associated with poor survival. Concentrations of 4 and 8 mmol/L NTCU were better tolerated and produced only significant levels of flat atypia. Squamous origin of the range of observed lesions was confirmed with IHC staining for cytokeratin 5/6, p63, thyroid transcription factor-1 (TTF-1), and Napsin-A. This study shows that topical application of high-dose NTCU produces endobronchial premalignant lesions with classic squamous characteristics and should allow for improved preclinical evaluation of potential chemopreventive agents. Cancer Prev Res; 5(2); 283–9. ©2011 AACR.
Data from Chemoprevention Meets Glucose Control
Authors: Engelman Jeffrey A. , Cantley Lewis C.
Published: March 2024

Abstract
The report by Memmott et al. (beginning on page 1066 in this issue of the journal) assessing the efficacy of the antidiabetes drug metformin in a mouse model of lung carcinogenesis suggests protective effects via two possible avenues: Decreased circulating insulin and insulin-like growth factor levels and energy stress leading to inhibition of mammalian target of rapamycin signaling. These potential mechanisms are discussed in this perspective, as are their implications for cancer prevention and therapy. Cancer Prev Res; 3(9); 1049–52. ©2010 AACR.