bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Patched1 Inhibits Epidermal Progenitor Cell Expansion and Basal Cell Carcinoma Formation by Limiting Igfbp2 Activity
Authors: Villani Rehan M. , Adolphe Christelle , Palmer James , Waters Michael J. , Wainwright Brandon J.
Published: April 2023

Abstract
Basal cell carcinoma (BCC) of the skin is the most common form of cancer, with the majority being caused by mutations in the Patched1 (Ptch1) gene, leading to activation of the Hedgehog (Hh) signaling pathway. Hh signaling is implicated in many tumor types; thus, defining the mechanisms by which Ptch1 regulates tissue proliferation is of paramount importance. Here, we show that the key role of Ptch1 in the skin is to limit the size of the epidermal stem/progenitor compartment and allow hair follicle differentiation. Specifically, loss of Ptch1 leads to the promotion of progenitor cell fate by increasing basal cell proliferation and limiting the progression of basal cells into differentiated hair follicle cell types. Our data indicate that BCCs likely result from hair follicle progenitor cells that, due to Hh signal activation, cannot progress through normal hair follicle differentiation. These data confirm the role of Ptch1 as a negative regulator of epidermal progenitor turnover and also show for the first time that Ptch1 plays a role in the differentiation of the hair follicle lineage. In addition, we show that insulin-like growth factor binding protein 2 (Igfbp2) is upregulated in both murine and human BCCs and that blocking Igfbp2 activity reduces the Hh-mediated expansion of epidermal progenitor cells. We propose that Igfbp2 mediates epidermal progenitor cell expansion and therefore represents an epidermal progenitor cell–specific target of Hh signaling that promotes BCC development. Cancer Prev Res; 3(10); 1222–34. ©2010 AACR.
Data from Isoangustone A, A Novel Licorice Compound, Inhibits Cell Proliferation by Targeting PI3K, MKK4, and MKK7 in Human Melanoma
Authors: Song Nu Ry , Lee Eunjung , Byun Sanguine , Kim Jong-Eun , Mottamal Madhusoodanan , Park Jung Han Yoon , Lim Soon Sung , Bode Ann M. , Lee Hyong Joo , Lee Ki Won , Dong Zigang
Published: April 2023

Abstract
Licorice root is known to possess various bioactivities, including anti-inflammatory and anticancer effects. Glycyrrhizin, a triterpene compound, is the most abundant constituent of dried licorice root. However, high intake or long-term consumption of glycyrrhizin causes several side effects, such as hypertension, hypertensive encephalopathy, and hypokalemia. Therefore, finding additional active compounds other than glycyrrhizin in licorice that exhibit anticancer effects is worthwhile. We found that isoangustone A (IAA), a novel flavonoid from licorice root, suppressed proliferation of human melanoma cells. IAA significantly blocked cell-cycle progression at the G1-phase and inhibited the expression of G1-phase regulatory proteins, including cyclins D1 and E in the SK-MEL-28 human melanoma cell line. IAA suppressed the phosphorylation of Akt, GSK-3β, and JNK1/2. IAA also bound to phosphoinositide 3-kinase (PI3K), MKK4, and MKK7, strongly inhibiting their kinase activities in an ATP-competitive manner. Moreover, in a xenograft mouse model, IAA significantly decreased tumor growth, volume, and weight of SK-MEL-28 xenografts. Collectively, these results suggest that PI3K, MKK4, and MKK7 are the primary molecular targets of IAA in the suppression of cell proliferation. This insight into the biologic actions of IAA provides a molecular basis for the potential development of a new chemotherapeutic agent. Cancer Prev Res; 6(12); 1293–303. ©2013 AACR.
Data from Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival
Authors: Busso-Lopes Ariane F. , Marchi Fábio A. , Kuasne Hellen , Scapulatempo-Neto Cristovam , Trindade-Filho José Carlos S. , de Jesus Carlos Márcio N. , Lopes Ademar , Guimarães Gustavo C. , Rogatto Silvia R.
Published: April 2023

Abstract
The molecular mechanisms underlying penile carcinoma are still poorly understood, and the detection of genetic markers would be of great benefit for these patients. In this study, we assessed the genomic profile aiming at identifying potential prognostic biomarkers in penile carcinoma. Globally, 46 penile carcinoma samples were considered to evaluate DNA copy-number alterations via array comparative genomic hybridization (aCGH) combined with human papillomavirus (HPV) genotyping. Specific genes were investigated by using qPCR, FISH, and RT-qPCR. Genomic alterations mapped at 3p and 8p were related to worse prognostic features, including advanced T and clinical stage, recurrence and death from the disease. Losses of 3p21.1–p14.3 and gains of 3q25.31–q29 were associated with reduced cancer-specific and disease-free survival. Genomic alterations detected for chromosome 3 (LAMP3, PPARG, TNFSF10 genes) and 8 (DLC1) were evaluated by qPCR. DLC1 and PPARG losses were associated with poor prognosis characteristics. Losses of DLC1 were an independent risk factor for recurrence on multivariate analysis. The gene-expression analysis showed downexpression of DLC1 and PPARG and overexpression of LAMP3 and TNFSF10 genes. Chromosome Y losses and MYC gene (8q24) gains were confirmed by FISH. HPV infection was detected in 34.8% of the samples, and 19 differential genomic regions were obtained related to viral status. At first time, we described recurrent copy-number alterations and its potential prognostic value in penile carcinomas. We also showed a specific genomic profile according to HPV infection, supporting the hypothesis that penile tumors present distinct etiologies according to virus status. Cancer Prev Res; 8(2); 149–56. ©2014 AACR.
Data from Chemoprevention of Azoxymethane/Dextran Sodium Sulfate–Induced Mouse Colon Carcinogenesis by Freeze-Dried Yam Sanyaku and Its Constituent Diosgenin
Authors: Miyoshi Noriyuki , Nagasawa Tomoki , Mabuchi Ryota , Yasui Yumiko , Wakabayashi Keiji , Tanaka Takuji , Ohshima Hiroshi
Published: April 2023

Abstract
The effects of sanyaku, a traditional Chinese medicine [freeze-dried powder of the yam tuber (Dioscorea)], and its major steroidal saponin constituent, diosgenin, on colon carcinogenesis were investigated. Male ICR mice were subjected to a single intraperitoneal injection of azoxymethane (AOM; 10 mg/kg body weight) followed by administration of 1.5% dextran sodium sulfate (DSS) in drinking water for 7 days to establish carcinogenesis. Commercial diosgenin or sanyaku, which contained diosgenin at 63.8 ± 1.2 mg/kg dry weight, was given in the diet at 20, 100, or 500 mg/kg for 17 weeks. Groups of mice that received diosgenin or sanyaku at all doses yielded significantly less number of colon tumors compared with the AOM/DSS-treated mice. Occurrence of colonic mucosal ulcer and dysplastic crypt induced by AOM/DSS treatment was also significantly decreased by the administration of diosgenin and sanyaku, which was in accordance with the significant reduction of AOM/DSS-mediated increases in expression of inflammatory cytokines such as IL-1β by diosgenin and sanyaku. Furthermore, elevated levels of serum triglyceride in the AOM/DSS-treated mice tended to be reduced in mice given diosgenin and sanyaku. Microarray and real-time reverse transcriptase PCR analyses revealed that diosgenin administration increased 12-fold the expression of lipoprotein lipase, which may contribute to reduced serum triglyceride levels. Other genes altered by diosgenin included those associated with antioxidative stress responses and apoptosis, such as heme oxygenase-1, superoxide dismutase-3, and caspase-6. Our results imply that the Chinese medicine sanyaku and the tubers of various yams containing diosgenin as food could be ingested to prevent colon carcinogenesis in humans. Cancer Prev Res; 4(6); 924–34. ©2011 AACR.
Data from Vaccine Prevention of Cancer: Can Endogenous Antigens Be Targeted?
Authors: Weiner Louis M. , Surana Rishi , Murray Joseph
Published: April 2023

Abstract
This perspective on the report by Beatty et al. in this issue of the journal (beginning on page 438) discusses the prevention of cancer through vaccination strategies that target antigens associated with tumor promotion and progression. Such approaches were first developed for treating cancer. We address cancer vaccination in the context of a mouse model of inflammatory bowel disease expressing MUC1, an epithelial mucin aberrantly expressed during chronic inflammation and in colorectal carcinogenesis, and in a broader context that includes the potential of targeting the tumor microenvironment for immunoprevention in humans. Obstacles in developing effective cancer vaccines, including antigen selection, immunoediting, and tumor-mediated immunosuppression, are also discussed. Cancer Prev Res; 3(4); 410–5. ©2010 AACR.
Data from Loss of miR125a Expression in a Model of K-ras–Dependent Pulmonary Premalignancy
Authors: Liclican Elvira L. , Walser Tonya C. , Hazra Saswati , Krysan Kostyantyn , Park Stacy J. , Pagano Paul C. , Gardner Brian K. , Larsen Jill E. , Minna John D. , Dubinett Steven M.
Published: April 2023

Abstract
Understanding the molecular pathogenesis of lung cancer is necessary to identify biomarkers/targets specific to individual airway molecular profiles and to identify options for targeted chemoprevention. Herein, we identify mechanisms by which loss of microRNA (miRNA)125a-3p (miR125a) contributes to the malignant potential of human bronchial epithelial cells (HBEC) harboring an activating point mutation of the K-ras proto-oncogene (HBEC K-ras). Among other miRNAs, we identified significant miR125a loss in HBEC K-ras lines and determined that miR125a is regulated by the PEA3 transcription factor. PEA3 is upregulated in HBEC K-ras cells, and genetic knockdown of PEA3 restores miR125a expression. From a panel of inflammatory/angiogenic factors, we identified increased CXCL1 and vascular endothelial growth factor (VEGF) production by HBEC K-ras cells and determined that miR125a overexpression significantly reduces K-ras–mediated production of these tumorigenic factors. miR125a overexpression also abrogates increased proliferation of HBEC K-ras cells and suppresses anchorage-independent growth (AIG) of HBEC K-ras/P53 cells, the latter of which is CXCL1-dependent. Finally, pioglitazone increases levels of miR125a in HBEC K-ras cells via PEA3 downregulation. In addition, pioglitazone and miR125a overexpression elicit similar phenotypic responses, including suppression of both proliferation and VEGF production. Our findings implicate miR125a loss in lung carcinogenesis and lay the groundwork for future studies to determine whether miR125a is a possible biomarker for lung carcinogenesis and/or a chemoprevention target. Moreover, our studies illustrate that pharmacologic augmentation of miR125a in K-ras–mutated pulmonary epithelium effectively abrogates several deleterious downstream events associated with the mutation. Cancer Prev Res; 7(8); 845–55. ©2014 AACR.
Data from Dietary Energy Balance Modulates Prostate Cancer Progression in Hi-Myc Mice
Authors: Blando Jorge , Moore Tricia , Hursting Stephen , Jiang Guiyu , Saha Achinto , Beltran Linda , Shen Jianjun , Repass John , Strom Sara , DiGiovanni John
Published: April 2023

Abstract
Male Hi-Myc mice were placed on three dietary regimens [30% calorie restriction (CR), overweight control (modified AIN76A with 10 kcal% fat), and a diet-induced obesity regimen (DIO) 60 kcal% fat]. All diet groups had approximately similar incidence of hyperplasia and low-grade prostatic intraepithelial neoplasia in the ventral prostate at 3 and 6 months of age. However, 30% CR significantly reduced the incidence of in situ adenocarcinomas at 3 months compared with the DIO group and at 6 months compared with both the overweight control and DIO groups. Furthermore, the DIO regimen significantly increased the incidence of adenocarcinoma with aggressive stromal invasion, as compared with the overweight control group (96% vs. 65%, respectively; P = 0.02) at the 6-month time point. In addition, at both 3 and 6 months, only in situ carcinomas were observed in mice maintained on the 30% CR diet. Relative to overweight control, DIO increased whereas 30% CR reduced activation of Akt, mTORC1, STAT3, and NFκB (p65) in ventral prostate. DIO also significantly increased (and 30% CR decreased) numbers of T-lymphocytes and macrophages in the ventral prostate compared with overweight control. The mRNA levels for interleukin (IL) 1α, IL1β, IL6, IL7, IL23, IL27, NFκB1 (p50), TNFα, and VEGF family members were significantly increased in the ventral prostate of the DIO group compared with both the overweight control and 30% CR diet groups. Collectively, these findings suggest that enhanced growth factor (Akt/mTORC1 and STAT3) and inflammatory (NFκB and cytokines) signaling may play a role in dietary energy balance effects on prostate cancer progression in Hi-Myc mice. Cancer Prev Res; 4(12); 2002–14. ©2011 AACR.
Data from UCP2 Knockout Suppresses Mouse Skin Carcinogenesis
Authors: Li Wenjuan , Zhang Chunjing , Jackson Kasey , Shen Xingui , Jin Rong , Li Guohong , Kevil Christopher G. , Gu Xin , Shi Runhua , Zhao Yunfeng
Published: April 2023

Abstract
Mitochondrial uncoupling (uncouples electron transport from ATP production) has recently been proposed as a novel survival mechanism for cancer cells, and reduction in free radical generation is the accepted mechanism of action. However, there is no direct evidence supporting that uncoupling proteins promote carcinogenesis. Herein, we examined whether mitochondrial uncoupling affects mouse skin carcinogenesis using uncoupling protein 2 (UCP2) homozygous knockout and wild-type mice. The results indicate that knockout of Ucp2 significantly reduced the formation of both benign (papilloma) and malignant (squamous cell carcinoma) tumors. UCP2 knockout did not cause increases in apoptosis during skin carcinogenesis. The rates of oxygen consumption were decreased only in the carcinogen-treated UCP2 knockout mice, whereas glycolysis was increased only in the carcinogen-treated wild-type mice. Finally, the levels of metabolites pyruvate, malate, and succinate showed different trends after carcinogen treatments between the wild-type and UCP2 knockout mice. Our study is the first to demonstrate that Ucp2 knockout suppresses carcinogenesis in vivo. Together with early studies showing that UCP2 is overexpressed in a number of human cancers, UCP2 could be a potential target for cancer prevention and/or therapy. Cancer Prev Res; 8(6); 487–91. ©2015 AACR.
Data from Dietary Patterns after Prostate Cancer Diagnosis in Relation to Disease-Specific and Total Mortality
Authors: Yang Meng , Kenfield Stacey A. , Van Blarigan Erin L. , Batista Julie L. , Sesso Howard D. , Ma Jing , Stampfer Meir J. , Chavarro Jorge E.
Published: April 2023

Abstract
Men diagnosed with nonmetastatic prostate cancer have a long life expectancy, and many die of unrelated causes. It is therefore important to know to what extent post-diagnostic diet may affect disease-specific and overall mortality. A total of 926 men participating in the Physicians' Health Study diagnosed with nonmetastatic prostate cancer completed diet questionnaires for a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years since questionnaire completion. Two post-diagnostic dietary patterns were identified: a Prudent pattern, characterized by higher intake of vegetables, fruits, fish, legumes, and whole grains; and a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains. Cox regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). During 8,093 person-years of follow-up, 333 men died, 56 (17%) of prostate cancer. The Western pattern was significantly related to a higher risk of prostate cancer–specific and all-cause mortality. Comparing men in the highest versus the lowest quartile of the Western pattern, the HRs were 2.53 (95% CI, 1.00–6.42; Ptrend = 0.02) for prostate cancer–specific mortality and 1.67 (95% CI, 1.16–2.42; Ptrend = 0.01) for all-cause mortality. The Prudent pattern was associated with a significantly lower all-cause mortality (HRQuartile 4 vs. Quartile 1: 0.64; 95% CI, 0.44–0.93; Ptrend = 0.02); the relationship with prostate cancer–specific mortality was inverse but not statistically significant. A post-diagnostic Western dietary pattern was associated with higher prostate cancer–specific and all-cause mortality, whereas a Prudent dietary pattern was related to lower all-cause mortality after prostate cancer diagnosis. Cancer Prev Res; 8(6); 545–51. ©2015 AACR.
Data from Lung Cancer Biomarkers: FISHing in the Sputum for Risk Assessment and Early Detection
Authors: Gomperts Brigitte N. , Spira Avrum , Elashoff David E. , Dubinett Steven M.
Published: April 2023

Abstract
This perspective on Varella-Garcia et al. (beginning on p. 447 in this issue of the journal) discusses the role of sputum-based biomarkers in the risk assessment and early detection of lung cancer. The importance of the detection of sputum epithelial chromosomal aneusomy by fluorescence in situ hybridization (FISH) as a potential risk or early-detection biomarker is discussed in the context of other biomarkers and models in lung carcinogenesis. The presently reported findings on FISH in sputum cells are an important contribution worthy of further investigation in defined clinical settings. Cancer Prev Res; 3(4); 420–3. ©2010 AACR.
Data from Epigallocatechin-gallate Suppresses Tumorigenesis by Directly Targeting Pin1
Authors: Urusova Darya V. , Shim Jung-Hyun , Kim Dong Joon , Jung Sung Keun , Zykova Tatyana A. , Carper Andria , Bode Ann M. , Dong Zigang
Published: April 2023

Abstract
The most active anticancer component in green tea is epigallocatechin-3-gallate (EGCG). The human peptidyl prolyl cis/trans isomerase (Pin1) plays a critical role in oncogenic signaling. Herein, we report the X-ray crystal structure of the Pin1/EGCG complex resolved at 1.9 Å resolution. Notably, the structure revealed the presence of EGCG in both the WW and PPIase domains of Pin1. The direct binding of EGCG with Pin1 was confirmed and the interaction inhibited Pin1 PPIase activity. In addition, proliferation of cells expressing Pin1 was inhibited and tumor growth in a xenograft mouse model was suppressed. The binding of EGCG with Arg17 in the WW domain prevented the binding of c-Jun, a well-known Pin1 substrate. EGCG treatment corresponded with a decreased abundance of cyclin D1 and diminution of 12-O-tetradecanoylphorbol-l3-acetate–induced AP-1 or NF-κB promoter activity in cells expressing Pin1. Overall, these results showed that EGCG directly suppresses the tumor-promoting effect of Pin1. Cancer Prev Res; 4(9); 1366–77. ©2011 AACR.
Data from A Multiplexable, Microfluidic Platform for the Rapid Quantitation of a Biomarker Panel for Early Ovarian Cancer Detection at the Point-of-Care
Authors: Shadfan Basil H. , Simmons Archana R. , Simmons Glennon W. , Ho Andy , Wong Jorge , Lu Karen H. , Bast Robert C. , McDevitt John T.
Published: April 2023

Abstract
Point-of-care (POC) diagnostic platforms have the potential to enable low-cost, large-scale screening. As no single biomarker is shed by all ovarian cancers, multiplexed biomarker panels promise improved sensitivity and specificity to address the unmet need for early detection of ovarian cancer. We have configured the programmable bio-nano-chip (p-BNC)—a multiplexable, microfluidic, modular platform—to quantify a novel multi-marker panel comprising CA125, HE4, MMP-7, and CA72-4. The p-BNC is a bead-based immunoanalyzer system with a credit-card–sized footprint that integrates automated sample metering, bubble and debris removal, reagent storage and waste disposal, permitting POC analysis. Multiplexed p-BNC immunoassays demonstrated high specificity, low cross-reactivity, low limits of detection suitable for early detection, and a short analysis time of 43 minutes. Day-to-day variability, a critical factor for longitudinally monitoring biomarkers, ranged between 5.4% and 10.5%, well below the biologic variation for all four markers. Biomarker concentrations for 31 late-stage sera correlated well (R2 = 0.71 to 0.93 for various biomarkers) with values obtained on the Luminex platform. In a 31 patient cohort encompassing early- and late-stage ovarian cancers along with benign and healthy controls, the multiplexed p-BNC panel was able to distinguish cases from controls with 68.7% sensitivity at 80% specificity. Utility for longitudinal biomarker monitoring was demonstrated with prediagnostic plasma from 2 cases and 4 controls. Taken together, the p-BNC shows strong promise as a diagnostic tool for large-scale screening that takes advantage of faster results and lower costs while leveraging possible improvement in sensitivity and specificity from biomarker panels. Cancer Prev Res; 8(1); 37–48. ©2014 AACR.
Data from Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-analysis Taking into Account Biases and Confounders
Authors: Gandini Sara , Puntoni Matteo , Heckman-Stoddard Brandy M. , Dunn Barbara K. , Ford Leslie , DeCensi Andrea , Szabo Eva
Published: April 2023

Abstract
Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52–0.90], although between-study heterogeneity was considerable (I2 = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54–0.81; I2 = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70–0.96 with I2 = 76% and SRR, 0.90; 95% CI, 0.89–0.91 with I2 = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. Cancer Prev Res; 7(9); 867–85. ©2014 AACR.
Data from Soy Isoflavone Supplementation for Breast Cancer Risk Reduction: A Randomized Phase II Trial
Authors: Khan Seema A. , Chatterton Robert T. , Michel Nancy , Bryk Michelle , Lee Oukseub , Ivancic David , Heinz Richard , Zalles Carola M. , Helenowski Irene B. , Jovanovic Borko D. , Franke Adrian A. , Bosland Maarten C. , Wang Jun , Hansen Nora M. , Bethke Kevin P. , Dew Alexander , Coomes Margerie , Bergan Raymond C.
Published: April 2023

Abstract
Soy isoflavone consumption may protect against breast cancer development. We conducted a phase IIB trial of soy isoflavone supplementation to examine its effect on breast epithelial proliferation and other biomarkers in the healthy high-risk breast. One hundred and twenty-six consented women underwent a random fine-needle aspiration (rFNA); those with 4,000 or more epithelial cells were randomized to a double-blind 6-month intervention of mixed soy isoflavones (PTIG-2535) or placebo, followed by repeat rFNA. Cells were examined for Ki-67 labeling index and atypia. Expression of 28 genes related to proliferation, apoptosis, and estrogenic effect was measured using quantitative reverse transcriptase PCR. Hormone and protein levels were measured in nipple aspirate fluid (NAF). All statistical tests were two-sided. Ninety-eight women were evaluable for Ki-67 labeling index. In 49 treated women, the median Ki-67 labeling index was 1.18 at entry and 1.12 post intervention, whereas in 49 placebo subjects, it was 0.97 and 0.92 (P for between-group change: 0.32). Menopausal stratification yielded similar results between groups, but within premenopausal soy-treated women, Ki-67 labeling index increased from 1.71 to 2.18 (P = 0.04). We saw no treatment effect on cytologic atypia or NAF parameters. There were significant increases in the expression of 14 of 28 genes within the soy, but not the control group, without significant between-group differences. Plasma genistein values showed excellent compliance. A 6-month intervention of mixed soy isoflavones in healthy, high-risk adult Western women did not reduce breast epithelial proliferation, suggesting a lack of efficacy for breast cancer prevention and a possible adverse effect in premenopausal women. Cancer Prev Res; 5(2); 309–19. ©2012 AACR.
Data from Clinical Trial of Acolbifene in Premenopausal Women at High Risk for Breast Cancer
Authors: Fabian Carol J. , Kimler Bruce F. , Zalles Carola M. , Phillips Teresa A. , Metheny Trina , Petroff Brian K. , Havighurst Thomas C. , Kim KyungMann , Bailey Howard H. , Heckman-Stoddard Brandy M.
Published: April 2023

Abstract
The purpose of this study was to assess the feasibility of using the selective estrogen receptor modulator (SERM) acolbifene as a breast cancer prevention agent in premenopausal women. To do so, we assessed change in proliferation in benign breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) as a primary endpoint, along with changes in other risk biomarkers and objective and subjective side effects as secondary endpoints. Twenty-five women with cytologic hyperplasia ± atypia and ≥2% of breast epithelial cells staining positive for Ki-67, received 20 mg acolbifene daily for 6–8 months, and then had benign breast tissue and blood risk biomarkers reassessed. Ki-67 decreased from a median of 4.6% [interquartile range (IQR), 3.1%–8.5%] at baseline to 1.4% (IQR, 0.6%–3.5%) after acolbifene (P < 0.001; Wilcoxon signed-rank test), despite increases in bioavailable estradiol. There were also significant decreases in expression (RT-qPCR) of estrogen-inducible genes that code for pS2, ERα, and progesterone receptor (P ≤ 0.026). There was no significant change in serum IGF1, IGFBP3, IGF1:IGFBP3 ratio, or mammographic breast density. Subjective side effects were minimal with no significant increase in hot flashes, muscle cramps, arthralgias, or fatigue. Objective measures showed a clinically insignificant decrease in lumbar spine bone density (DEXA) and an increase in ovarian cysts but no change in endometrial thickness (sonography). In summary, acolbifene was associated with favorable changes in benign breast epithelial cell proliferation and estrogen-inducible gene expression but minimal side effects, suggesting a phase IIB placebo-controlled trial evaluating it further for breast cancer prevention. Cancer Prev Res; 8(12); 1146–55. ©2015 AACR.
Data from Altered Histology Provides a Positive Clinical Signal in the Bronchial Epithelium
Authors: Szabo Eva
Published: April 2023

Abstract
The history of lung cancer chemoprevention trials has been uniformly disappointing in that the large phase III studies showed no effect or harm in actively smoking participants, and smaller phase II studies have also been negative. In this issue of the journal (beginning on page 793), Keith and colleagues report their randomized, placebo-controlled trial of the oral prostacyclin analogue iloprost, the first trial to show an improvement in bronchial histology (i.e., regression), which occurred in former, but not current, smokers with sputum atypia. This Perspective discusses the strength of the clinical signal provided by this observation and its implications for further drug development. Cancer Prev Res; 4(6); 775–8. ©2011 AACR.
Data from Sulindac Metabolites Induce Proteosomal and Lysosomal Degradation of the Epidermal Growth Factor Receptor
Authors: Pangburn Heather A. , Ahnen Dennis J. , Rice Pamela L.
Published: April 2023

Abstract
The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases. In response to ligand, EGFR is internalized and degraded by the ubiquitin-proteasome/lysosome pathway. We previously reported that metabolites of the nonsteroidal anti-inflammatory drug sulindac downregulate the expression of EGFR and inhibit basal and EGF-induced EGFR signaling through extracellular signal–regulated kinase 1/2. We now have evaluated the mechanisms of sulindac metabolite–induced downregulation of EGFR. EGF-induced downregulation of EGFR occurs within 10 minutes and lasts for 24 hours. By contrast, downregulation of EGFR by sulindac sulfide and sulindac sulfone was first evident at 4 and 24 hours, respectively, with maximal downregulation at 72 hours. Pretreatment with either the lysosomal inhibitor chloroquine or the proteosomal inhibitor MG132 blocked sulindac metabolite–induced downregulation of EGFR. Sulindac metabolites also increased the ubiquitination of EGFR. Whereas sulindac metabolites inhibited phosphorylation of EGFR pY1068, they increased phosphorylation of EGFR pY1045, the docking site where c-Cbl binds, thereby enabling receptor ubiquitination and degradation. Immunofluorescence analysis of EGF and EGFR distribution confirmed the biochemical observations that sulindac metabolites alter EGFR localization and EGFR internalization in a manner similar to that seen with EGF treatment. Expression of ErbB family members HER2 and HER3 was also downregulated by sulindac metabolites. We conclude that downregulation of EGFR expression by sulindac metabolites is mediated via lysosomal and proteosomal degradation that may be due to drug-induced phosphorylation at pY1045 with resultant ubiquitination of EGFR. Thus, sulindac metabolite–induced downregulation of EGFR seems to be mediated through mechanism(s) similar, at least in part, to those involved in EGF-induced downregulation of EGFR. Cancer Prev Res; 3(4); 560–72. ©2010 AACR.
Data from The Influence of UGT1A6 Variants and Aspirin Use in a Randomized Trial of Celecoxib for Prevention of Colorectal Adenoma
Authors: Chan Andrew T. , Hsu Meier , Zauber Ann G. , Hawk Ernest T. , Bertagnolli Monica M.
Published: April 2023

Abstract
Aspirin and celecoxib prevent colorectal adenoma recurrence. Genetic variants in the UGT1A6 enzyme are associated with delayed aspirin metabolism and greater chemopreventive efficacy. We examined the effect of combining aspirin and celecoxib in relation to UGT1A6 T181A and R184S variants among 1,647 patients in the Adenoma Prevention with Celecoxib (APC) trial who were stratified according to the use of low-dose aspirin after removal of adenomas and randomized to placebo, 200-mg twice daily, or 400-mg twice daily celecoxib for 3 years. Patients underwent follow-up colonoscopies at 1 and 3 years to assess on-treatment efficacy. At 5 years, 538 patients underwent a colonoscopy to assess risk of recurrence after treatment was discontinued for at least 1 year. During treatment, the relative risk (RR) of recurrent adenoma was 0.68 [95% confidence interval (CI), 0.59–0.79] for 200-mg twice daily celecoxib and 0.54 (95% CI, 0.46–0.64) for 400-mg twice daily celecoxib compared with placebo. Aspirin use was not independently associated with recurrent adenoma (RR, 0.98, 95% CI, 0.86–1.15). These results did not vary according to UGT1A6 genotype. However, among those with a variant UGT1A6 genotype on aspirin, the RR of adenoma was 1.60 (95% CI, 0.81–3.15) after withdrawal of 200-mg twice daily and 1.98 (95% CI, 1.06–3.70) after withdrawal of 400-mg twice daily celecoxib compared with withdrawal of placebo. In contrast, there was no increased risk associated with discontinuing celecoxib among any other groups. Concurrent use of low-dose aspirin does not influence the efficacy of celecoxib in adenoma prevention. However, discontinuing celecoxib among aspirin-using individuals who initially developed adenoma despite a UGT1A6 variant genotype resulted in rapid reemergence of disease. Cancer Prev Res; 5(1); 61–72. ©2011 AACR.
Data from The Heat Shock Protein 90 Inhibitor, (−)-Epigallocatechin Gallate, Has Anticancer Activity in a Novel Human Prostate Cancer Progression Model
Authors: Moses Michael A. , Henry Ellen C. , Ricke William A. , Gasiewicz Thomas A.
Published: April 2023

Abstract
(−)-Epigallocatechin gallate (EGCG), a major tea polyphenol, elicits anticancer effects. However, the mechanism of action is not fully understood. Our laboratory previously showed that EGCG inhibits heat shock protein 90 (HSP90). We used nontumorigenic (NT), tumorigenic, and metastatic cancer cells from a novel human prostate cancer progression model to test the hypotheses that certain stages are more or less sensitive to EGCG and that sensitivity is related to HSP90 inhibition. Treatment of cells with EGCG, novobiocin, or 17-AAG resulted in more potent cytotoxic effects on tumorigenic and metastatic cells than NT cells. When tumorigenic or metastatic cells were grown in vivo, mice supplemented with 0.06% EGCG in drinking water developed significantly smaller tumors than untreated mice. Furthermore, EGCG prevented malignant transformation in vivo using the full prostate cancer model. To elucidate the mechanism of EGCG action, we performed binding assays with EGCG-Sepharose, a C-terminal HSP90 antibody, and HSP90 mutants. These experiments revealed that EGCG-Sepharose bound more HSP90 from metastatic cells compared with NT cells and binding occurred through the HSP90 C-terminus. In addition, EGCG bound HSP90 mutants that mimic both complexed and uncomplexed HSP90. Consistent with HSP90 inhibitory activity, EGCG, novobiocin, and 17-AAG induced changes in HSP90-client proteins in NT cells and larger differences in metastatic cells. These data suggest that EGCG may be efficacious for the treatment of prostate cancer because it preferentially targets cancer cells and inhibits a molecular chaperone supportive of the malignant phenotype. Cancer Prev Res; 8(3); 249–57. ©2015 AACR.
Data from Nrf2 Activation Protects against Solar-Simulated Ultraviolet Radiation in Mice and Humans
Authors: Knatko Elena V. , Ibbotson Sally H. , Zhang Ying , Higgins Maureen , Fahey Jed W. , Talalay Paul , Dawe Robert S. , Ferguson James , Huang Jeffrey T.-J. , Clarke Rosemary , Zheng Suqing , Saito Akira , Kalra Sukirti , Benedict Andrea L. , Honda Tadashi , Proby Charlotte M. , Dinkova-Kostova Albena T.
Published: April 2023

Abstract
The transcription factor Nrf2 determines the ability to adapt and survive under conditions of electrophilic, oxidative, and inflammatory stress by regulating the expression of elaborate networks comprising nearly 500 genes encoding proteins with versatile cytoprotective functions. In mice, disruption of Nrf2 increases susceptibility to carcinogens and accelerates disease pathogenesis. Paradoxically, Nrf2 is upregulated in established human tumors, but whether this upregulation drives carcinogenesis is not known. Here we show that the incidence, multiplicity, and burden of solar-simulated UV radiation–mediated cutaneous tumors that form in SKH-1 hairless mice in which Nrf2 is genetically constitutively activated are lower than those that arise in their wild-type counterparts. Pharmacologic Nrf2 activation by topical biweekly applications of small (40 nmol) quantities of the potent bis(cyano enone) inducer TBE-31 has a similar protective effect against solar-simulated UV radiation in animals receiving long-term treatment with the immunosuppressive agent azathioprine. Genetic or pharmacologic Nrf2 activation lowers the expression of the pro-inflammatory factors IL6 and IL1β, and COX2 after acute exposure of mice to UV radiation. In healthy human subjects, topical applications of extracts delivering the Nrf2 activator sulforaphane reduced the degree of solar-simulated UV radiation–induced skin erythema, a quantifiable surrogate endpoint for cutaneous damage and skin cancer risk. Collectively, these data show that Nrf2 is not a driver for tumorigenesis even upon exposure to a very potent and complete carcinogen and strongly suggest that the frequent activation of Nrf2 in established human tumors is a marker of metabolic adaptation. Cancer Prev Res; 8(6); 475–86. ©2015 AACR.
Data from Effect of Combined Treatment with Ursolic Acid and Resveratrol on Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate
Authors: Cho Jiyoon , Rho Okkyung , Junco Jacob , Carbajal Steve , Siegel Dionicio , Slaga Thomas J. , DiGiovanni John
Published: April 2023

Abstract
In this study, the effects of combining ursolic acid + resveratrol, for possible combined inhibitory effects on skin tumor promotion, were evaluated. Ursolic acid, resveratrol, and the combination of ursolic acid + resveratrol were applied topically prior to 12-O-tetracanoylphorbol-13-acetate (TPA) treatment on mouse skin to examine their effect on TPA-induced signaling pathways, epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion. The combination of ursolic acid + resveratrol produced a greater inhibition of TPA-induced epidermal hyperproliferation. The combination of ursolic acid + resveratrol inhibited TPA-induced signaling pathways, including EGFR, STAT3, Src, Akt, Cox-2, Fas, NF-κB, p38 MAPK, c-Jun, and JNK1/2 while increasing levels of tumor suppressors, such as p21 and PDCD4, to a greater extent compared with the groups treated with the individual compounds. Ursolic acid + resveratrol also induced a dramatic increase of p-AMPK-αThr172. Combined treatment with ursolic acid + resveratrol resulted in a greater inhibition of expression of proinflammatory cytokines, including Il1a, Il1b, and Il22. Furthermore, NF-κB, Egr-1, and AP-1 DNA binding activities after TPA treatment were dramatically decreased by the combination of ursolic acid + resveratrol. Treatment with ursolic acid + resveratrol during skin tumor promotion with TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the greater ability of the combination of ursolic acid + resveratrol to inhibit skin tumor promotion was due to the greater inhibitory effects on growth factor and inflammatory signaling, skin inflammation, and epidermal hyperproliferation induced by TPA treatment. Cancer Prev Res; 8(9); 817–25. ©2015 AACR.
Data from A Randomized Controlled Trial of Celecoxib to Prevent Recurrence of Nonmuscle-Invasive Bladder Cancer
Authors: Sabichi Anita L. , Lee J. Jack , Grossman H. Barton , Liu Suyu , Richmond Ellen , Czerniak Bogdan A. , De la Cerda Jorge , Eagle Craig , Viner Jaye L. , Palmer J. Lynn , Lerner Seth P.
Published: April 2023

Abstract
Significant morbidity and expense result from frequent recurrences of nonmuscle-invasive bladder cancer (NMIBC) after standard treatment, and carcinoma in situ (Tis) is a poor prognostic factor. Predicated on observational and preclinical data strongly supporting cyclooxygenase-2 (COX-2) in the pathogenesis, and the activity of COX-2 inhibitors, in bladder cancer, we conducted a randomized, double-blind, placebo-controlled trial to determine whether celecoxib could reduce the time-to-recurrence (TTR) in NMIBC patients at high risk for recurrence. A total of 146 patients were randomized to celecoxib (200 mg) or placebo orally twice daily for at least 12 months. The average treatment duration was 1.25 years. Primary intent-to-treat analysis revealed celecoxib did not statistically significantly prolong TTR compared with placebo (P = 0.17, log rank) with a median follow-up of 2.49 years. The recurrence-free rate at 12 months with celecoxib was 88% (95% CI: 0.81–0.96) versus 78% (95% CI: 0.69–0.89) with placebo. After controlling for covariates with Cox regression analysis, recurrence rates did not differ between the two study arms (HR = 0.69; 95% CI: 0.37–1.29). However, celecoxib had a marginally significant effect on reducing metachronous recurrences (vs. placebo) with HR of 0.56 (95% CI: 0.3–1.06; P = 0.075). Celecoxib was well tolerated, with similar adverse events and quality-of-life in both arms. Our clinical trial results do not show a clinical benefit for celecoxib in preventing NMIBC recurrence but further investigation of COX-2 inhibitors in this setting is warranted. Cancer Prev Res; 4(10); 1580–9. ©2011 AACR.
Data from The Effects of Varying Dietary Carbohydrate and Fat Content on Survival in a Murine LNCaP Prostate Cancer Xenograft Model
Authors: Mavropoulos John C. , Buschemeyer W. Cooper , Tewari Alok K. , Rokhfeld Dmitriy , Pollak Michael , Zhao Yunhua , Febbo Phillip G. , Cohen Pinchas , Hwang David , Devi Gayathri , Demark-Wahnefried Wendy , Westman Eric C. , Peterson Bercedis L. , Pizzo Salvatore V. , Freedland Stephen J.
Published: April 2023

Abstract
Purpose: Numerous dietary factors elevate serum levels of insulin and insulin-like growth factor I (IGF-I), both potent prostate cancer mitogens. We tested whether varying dietary carbohydrate and fat, without energy restriction relative to comparison diets, would slow tumor growth and reduce serum insulin, IGF-I, and other molecular mediators of prostate cancer in a xenograft model.

Experimental Design: Individually caged male severe combined immunodeficient mice (n = 130) were randomly assigned to one of three diets (described as percent total calories): very high-fat/no-carbohydrate ketogenic diet (NCKD: 83% fat, 0% carbohydrate, 17% protein), low-fat/high-carbohydrate diet (LFD: 12% fat, 71% carbohydrate, 17% protein), or high-fat/moderate-carbohydrate diet (MCD: 40% fat, 43% carbohydrate, 17% protein). Mice were fed to maintain similar average body weights among groups. Following a preliminary feeding period, mice were injected with 1 × 106 LNCaP cells (day 0) and sacrificed when tumors were ≥1,000 mm3.

Results: Two days before tumor injection, median NCKD body weight was 2.4 g (10%) and 2.1 g (8%) greater than the LFD and MCD groups, respectively (P < 0.0001). Diet was significantly associated with overall survival (log-rank P = 0.004). Relative to MCD, survival was significantly prolonged for the LFD (hazard ratio, 0.49; 95% confidence interval, 0.29-0.79; P = 0.004) and NCKD groups (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.02). Median serum insulin, IGF-I, IGF-I/IGF binding protein-1 ratio, and IGF-I/IGF binding protein-3 ratio were significantly reduced in NCKD relative to MCD mice. Phospho-AKT/total AKT ratio and pathways associated with antiapoptosis, inflammation, insulin resistance, and obesity were also significantly reduced in NCKD relative to MCD tumors.

Conclusions: These results support further preclinical exploration of carbohydrate restriction in prostate cancer and possibly warrant pilot or feasibility testing in humans.
Data from Alterations of Cyclooxygenase-2 Methylation Levels Before and After Intervention Trial to Prevent Gastric Cancer in a Chinese Population
Authors: Zhang Yang , Zeng Hong-Mei , Nie Xiao-Rui , Zhang Lian , Ma Jun-Ling , Li Ji-You , Pan Kai-Feng , You Wei-Cheng
Published: April 2023

Abstract
To explore the epigenetic mechanisms underlying the effects of anti-Helicobacter pylori (H. pylori) alone and combined with COX-2 inhibitor (celecoxib), we dynamically evaluated the associations between COX-2 methylation alterations and gastric lesion evolution during the process of interventions. In a total of 809 trial participants COX-2 methylation levels were quantitatively detected before and after treatment. The self-comparison at the same stomach site for each subject showed significant methylation alteration differences among intervention groups (P < 0.001). With placebo group as reference, COX-2 methylation levels were decreased in anti-H. pylori [OR, 3.30; 95% confidence interval (CI), 2.16–5.02], celecoxib (OR, 2.04; 95% CI, 1.36–3.07), and anti-H. pylori followed by celecoxib (OR, 2.10; 95% CI, 1.38–3.17) groups. When stratified by baseline histology, the three active arms significantly decreased COX-2 methylation levels in indefinite dysplasia/dysplasia subjects, and ORs were 3.65 (95% CI, 1.96–6.80) for anti-H. pylori, 2.43 (95% CI 1.34–4.39) for celecoxib, and 2.80 (95% CI, 1.52–5.15) for anti-H. pylori followed by celecoxib, respectively. No additive effect on COX-2 methylation was found for anti-H. pylori followed by celecoxib than two treatments alone. Compared with subjects without methylation reduction, higher opportunity for gastric lesion regression was found in subjects with decreased COX-2 methylation levels, especially for indefinite dysplasia/dysplasia subjects (OR, 1.92; 95% CI, 1.03–3.60). These findings suggest that anti-H. pylori or celecoxib treatment alone could decrease COX-2 methylation levels in gastric mucosa. COX-2 methylation alteration was associated with the regression of indefinite dysplasia/dysplasia, which might serve as a potential biomarker for chemoprevention efficacy. Cancer Prev Res; 9(6); 484–90. ©2016 AACR.
Data from STAT3 as a Chemoprevention Target in Carcinogen-Induced Head and Neck Squamous Cell Carcinoma
Authors: Peyser Noah D. , Wang Lin , Zeng Yan , Acquafondata Marie , Freilino Maria , Li Hua , Sen Malabika , Gooding William E. , Satake Masanobu , Wang Zhenghe , Johnson Daniel E. , Grandis Jennifer R.
Published: April 2023

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal disease due, in large part, to a high rate of second primary tumor (SPT) formation. The 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis provides a robust system in which to study chemopreventive agents in the context of chemically induced HNSCC tumors. STAT3 is a potent oncogene that is hyperactivated by tyrosine phosphorylation early in HNSCC carcinogenesis and is a rational therapeutic target. We recently reported that loss-of-function of the STAT3 phosphatase PTPRT promotes STAT3 activation in HNSCC tumors and preclinical models and may serve as a predictive biomarker of response to STAT3 inhibitors, including the small-molecule Stattic. We therefore investigated the hypothesis that Ptprt-knockout (KO) mice would be more susceptible to 4-NQO–induced oral carcinogenesis and more sensitive to Stattic-mediated chemoprevention compared with wild-type (WT) mice. Herein, we demonstrate that Ptprt WT and KO mice develop similar spectra of HNSCC disease severity upon 12 weeks of 4-NQO administration, with no apparent effect of Ptprt genotype on carcinogenesis or treatment outcome. Targeting of STAT3 with Stattic resulted in a chemopreventive effect against 4-NQO–induced oral cancer (P = 0.0402). While these results do not support a central role for PTPRT in 4-NQO–induced HNSCC carcinogenesis, further investigation of STAT3 as a chemoprevention target in this cancer is warranted. Cancer Prev Res; 9(8); 657–63. ©2016 AACR.