bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PPARγ Agonists Target Aromatase Via Both PGE2 and BRCA1
Authors: Margalit Ofer , Wang Dingzhi , DuBois Raymond N.
Published: March 2024

Abstract
Obesity is a well-recognized risk factor for postmenopausal breast cancer. Although the underlying mechanisms are not clearly defined, aromatase is thought to play a pivotal role in connecting obesity-associated inflammation with postmenopausal breast cancer. It has been well established that both the proinflammatory prostaglandin E2 (PGE2) and the BRCA1 tumor-suppressor gene regulate aromatase expression. In this issue of the journal (beginning on p. 1183), Subbaramaiah and colleagues improve our understanding of the molecular mechanisms by which PPARγ inhibits aromatase expression. They found that pioglitazone, a PPARγ agonist, inhibited aromatase expression by inhibition of PGE2 signaling and upregulation of BRCA1. Their findings provide potential targets for preventing or treating obesity-related breast cancer. Cancer Prev Res; 5(10); 1169–72. ©2012 AACR.
Data from Making Sense of Missense in Lynch Syndrome: The Clinical Perspective
Authors: Lynch Henry T. , Jascur Thomas , Lanspa Stephen , Boland C. Richard
Published: March 2024

Abstract
The DNA mismatch repair (MMR) system provides critical genetic housekeeping, and its failure is associated with tumorigenesis. Through distinct domains on the DNA MMR proteins, the system recognizes and repairs errors occurring during DNA synthesis, but signals apoptosis when the DNA damage cannot be repaired. Certain missense mutations in the MMR genes can selectively alter just one of these functions. This affects the clinical features of tumors associated with defective DNA MMR activity. New work reported by Xie et al. in this issue of the journal (beginning on page 1409) adds to the understanding of DNA MMR. Cancer Prev Res; 3(11); 1371–4. ©2010 AACR.
Data from Dietary Methyl Donor Depletion Protects Against Intestinal Tumorigenesis in ApcMin/+ Mice
Authors: Kadaveru Krishna , Protiva Petr , Greenspan Emily J. , Kim Young-In , Rosenberg Daniel W.
Published: March 2024

Abstract
Despite recent population data, the influence of dietary folate supplementation on colon cancer risk remains controversial. This study examines the effects of folate deficiency, in combination with choline, methionine, and vitamin B12 depletion, on intestinal tumorigenesis in ApcMin/+ mice. Methyl donor sufficient (MDS) and deficient (MDD) diets were started at five or 10 weeks of age and tumors evaluated at 16 weeks. MDD suppressed intestinal tumor formation in ApcMin/+ mice (∼80%) when started at five weeks of age. The protective effect was lost when MDD was initiated at 10 weeks of age, indicating an important time dependency on cancer suppression. Concomitant with cancer protection, MDD restricted body weight gain. Therefore, a second study was conducted in which MDS was given ad libitum or pair-fed with MDD. Although small intestinal tumors were reduced 54% in pair-fed MDS mice, MDD caused a further reduction (96%). In colon, although MDD did not affect tumor numbers, tumor size was reduced. Gene expression profiling of normal-appearing colonic mucosa after 11 weeks on MDD identified a total of 493 significantly downregulated genes relative to the MDS group. Pathway analysis placed many of these genes within general categories of inflammatory signaling and cell-cycle regulation, consistent with recently published human data obtained during folate depletion. Further studies are warranted to investigate the complex interplay of methyl donor status and cancer protection in high-risk populations. Cancer Prev Res; 5(7); 911–20. ©2012 AACR.
Data from Cyclooxygenase-2 Generates the Endogenous Mutagen trans-4-Hydroxy-2-nonenal in Enterococcus faecalis–Infected Macrophages
Authors: Wang Xingmin , Allen Toby D. , Yang Yonghong , Moore Danny R. , Huycke Mark M.
Published: March 2024

Abstract
Infection of macrophages by the human intestinal commensal Enterococcus faecalis generates DNA damage and chromosomal instability in mammalian cells through bystander effects. These effects are characterized by clastogenesis and damage to mitotic spindles in target cells and are mediated, in part, by trans-4-hydroxy-2-nonenal (4-HNE). In this study, we investigated the role of COX and lipoxygenase (LOX) in producing this reactive aldehyde using E. faecalis–infected macrophages and interleukin (IL)-10–knockout mice colonized with this commensal. 4-HNE production by E. faecalis–infected macrophages was significantly reduced by COX and LOX inhibitors. The infection of macrophages led to decreased Cox1 and Alox5 expression whereas COX-2 and 4-HNE increased. Silencing Alox5 and Cox1 with gene-specific siRNAs had no effect on 4-HNE production. In contrast, silencing Cox2 significantly decreased 4-HNE production by E. faecalis–infected macrophages. Depleting intracellular glutathione increased 4-HNE production by these cells. Next, to confirm COX-2 as a source for 4-HNE, we assayed the products generated by recombinant human COX-2 and found 4-HNE in a concentration-dependent manner using arachidonic acid as a substrate. Finally, tissue macrophages in colon biopsies from IL-10–knockout mice colonized with E. faecalis were positive for COX-2 by immunohistochemical staining. This was associated with increased staining for 4-HNE protein adducts in surrounding stroma. These data show that E. faecalis, a human intestinal commensal, can trigger macrophages to produce 4-HNE through COX-2. Importantly, it reinforces the concept of COX-2 as a procarcinogenic enzyme capable of damaging DNA in target cells through bystander effects that contribute to colorectal carcinogenesis. Cancer Prev Res; 6(3); 206–16. ©2013 AACR.
Data from Dietary Polyphenols Suppress Elevated Levels of Proinflammatory Mediators and Aromatase in the Mammary Gland of Obese Mice
Authors: Subbaramaiah Kotha , Sue Erika , Bhardwaj Priya , Du Baoheng , Hudis Clifford A. , Giri Dilip , Kopelovich Levy , Zhou Xi Kathy , Dannenberg Andrew J.
Published: March 2024

Abstract
In postmenopausal women, obesity is a risk factor for the development of hormone receptor–positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity–inflammation–aromatase axis. This obesity-induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose tissue. CLS occur in association with NF-κB activation, elevated levels of proinflammatory mediators, and increased aromatase expression. Saturated fatty acids released from adipocytes have been linked to obesity-related white adipose tissue inflammation. Here we found that stearic acid, a prototypic saturated fatty acid, stimulated Akt-dependent activation of NF-κB resulting in increased levels of proinflammatory mediators [TNF-α, interleukin (IL)-1β, COX-2] in macrophages leading, in turn, to the induction of aromatase. Several polyphenols (resveratrol, curcumin, epigallocatechin gallate) blocked these inductive effects of stearic acid. Zyflamend, a widely used polyherbal preparation that contains numerous polyphenols, possessed similar suppressive effects. In a mouse model of obesity, treatment with Zyflamend suppressed levels of phospho-Akt, NF-κB binding activity, proinflammatory mediators, and aromatase in the mammary gland. Collectively, these results suggest that targeting the activation of NF-κB is a promising approach for reducing levels of proinflammatory mediators and aromatase in inflamed mouse mammary tissue. Further investigation in obese women is warranted. Cancer Prev Res; 6(9); 886–97. ©2013 AACR.
Data from Accuracy of In Vivo Multimodal Optical Imaging for Detection of Oral Neoplasia
Authors: Pierce Mark C. , Schwarz Richard A. , Bhattar Vijayashree S. , Mondrik Sharon , Williams Michelle D. , Lee J. Jack , Richards-Kortum Rebecca , Gillenwater Ann M.
Published: March 2024

Abstract
If detected early, oral cancer is eminently curable. However, survival rates for oral cancer patients remain low, largely due to late-stage diagnosis and subsequent difficulty of treatment. To improve clinicians' ability to detect early disease and to treat advanced cancers, we developed a multimodal optical imaging system (MMIS) to evaluate tissue in situ, at macroscopic and microscopic scales. The MMIS was used to measure 100 anatomic sites in 30 patients, correctly classifying 98% of pathologically confirmed normal tissue sites, and 95% of sites graded as moderate dysplasia, severe dysplasia, or cancer. When used alone, MMIS classification accuracy was 35% for sites determined by pathology as mild dysplasia. However, MMIS measurements correlated with expression of candidate molecular markers in 87% of sites with mild dysplasia. These findings support the ability of noninvasive multimodal optical imaging to accurately identify neoplastic tissue and premalignant lesions. This in turn may have considerable impact on detection and treatment of patients with oral cancer and other epithelial malignancies. Cancer Prev Res; 5(6); 801–9. ©2012 AACR.
Data from Selective PGE2 Suppression Inhibits Colon Carcinogenesis and Modifies Local Mucosal Immunity
Authors: Nakanishi Masako , Menoret Antoine , Tanaka Takuji , Miyamoto Shingo , Montrose David C. , Vella Anthony T. , Rosenberg Daniel W.
Published: March 2024

Abstract
Prostaglandin E2 (PGE2) is a bioactive lipid that mediates a wide range of physiologic effects and plays a central role in inflammation and cancer. PGE2 is generated from arachidonic acid by the sequential actions of the COX and terminal synthases (PGES). Increased levels of COX-2, with a concomitant elevation of PGE2, are often found in colorectal cancers (CRC), providing the rationale for the use of COX-2 inhibitors for chemoprevention. Despite their proven efficacy in cancer prevention, however, COX-2 inhibitors exhibit dose-dependent toxicities that are mediated in part by their nonspecific reduction of essential prostanoids, thus limiting their chemopreventive benefit. To achieve enhanced specificity, recent efforts have been directed toward targeting the inducible terminal synthase in the production of PGE2, microsomal PGES (mPGES-1). In the present study, we show that genetic deletion of mPGES-1 affords significant protection against carcinogen-induced colon cancer. mPGES-1 gene deletion results in an about 80% decrease in tumor multiplicity and up to a 90% reduction in tumor load in the distal colon of azoxymethane (AOM)-treated mice. Associated with the striking cancer suppression, we have identified a critical role for PGE2 in the control of immunoregulatory cell expansion (FoxP3-positive regulatory T cells) within the colon-draining mesenteric lymph nodes, providing a potential mechanism by which suppression of PGE2 may protect against CRC. These results provide new insights into how PGE2 controls antitumor immunity. Cancer Prev Res; 4(8); 1198–208. ©2011 AACR.
Data from Colorectal Adenoma Stem-like Cell Populations: Associations with Adenoma Characteristics and Metachronous Colorectal Neoplasia
Authors: Bartley Angela N. , Parikh Nila , Hsu Chiu-Hsieh , Roe Denise J. , Buckmeier Julie A. , Corley Lynda , Phipps Ron A. , Gallick Gary , Lance Peter , Thompson Patricia A. , Hamilton Stanley R.
Published: March 2024

Abstract
Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma (“recurrence”), has not been studied extensively. We evaluated the expression of aldehyde dehydrogenase isoform 1A1 (ALDH1A1), a putative stem cell marker, in baseline adenomas from the placebo arm of chemoprevention trial participants with colonoscopic follow-up. An exploratory set of 20 baseline adenomas was analyzed by ALDH1A1 immunohistochemistry with morphometry, and a replication set of 89 adenomas from 76 high-risk participants was evaluated by computerized image analysis. ALDH1A1-labeling indices (ALI) were similar across patient characteristics and in advanced and nonadvanced adenomas. There was a trend toward higher ALIs in adenomas occurring in the right than left colon (P = 0.09). ALIs of synchronous adenomas were correlated (intraclass correlation coefficient 0.67). Participants in both sample sets who developed a metachronous adenoma had significantly higher ALIs in their baseline adenoma than participants who remained adenoma free. In the replication set, the adjusted odds for metachronous adenoma increased 1.46 for each 10% increase in ALIs (P = 0.03). A best-fit algorithm–based cutoff point of 22.4% had specificity of 75.0% and positive predictive value of 70.0% for metachronous adenoma development. A larger population of ALDH1A1-expressing cells in an adenoma is associated with a higher risk for metachronous adenoma, independent of adenoma size or histopathology. If confirmed, ALDH1A1 has potential as a novel biomarker in risk assessment and as a potential stem cell target for chemoprevention. Cancer Prev Res; 6(11); 1162–70. ©2013 AACR.
Data from Skin Deep and Deeper: Multiple Pathways in Basal Cell Carcinogenesis
Authors: Peacock Craig D. , Rudin Charles M.
Published: March 2024

Abstract
This perspective places the report by Villani et al. that appears in this issue of the journal (beginning on page 1222) in the context of recent work showing an intersection between two important developmental pathways implicated in oncogenesis: the hedgehog and insulin-like growth factor (IGF) pathways. Villani et al. define a key role for the IGF regulatory protein Igfbp2 in a genetic model of basal cell carcinogenesis driven by targeted constitutive activation of hedgehog signaling. Placed in the framework of other recently published work, the observations of Villani et al. both raise questions about the cell of origin for basal cell cancers and define additional putative therapeutic and preventive targets for this disease. Cancer Prev Res; 3(10); 1213–6. ©2010 AACR.
Data from The UK Lung Screen (UKLS): Demographic Profile of First 88,897 Approaches Provides Recommendations for Population Screening
Authors: McRonald Fiona E. , Yadegarfar Ghasem , Baldwin David R. , Devaraj Anand , Brain Kate E. , Eisen Tim , Holemans John A. , Ledson Martin , Screaton Nicholas , Rintoul Robert C. , Hands Christopher J. , Lifford Kate , Whynes David , Kerr Keith M. , Page Richard , Parmar Mahesh , Wald Nicholas , Weller David , Williamson Paula R. , Myles Jonathan , Hansell David M. , Duffy Stephen W. , Field John K.
Published: March 2024

Abstract
The UK Lung Cancer Screening trial (UKLS) aims to evaluate low-dose computed tomography (LDCT) lung cancer population screening in the United Kingdom. In UKLS, a large population sample ages 50 to 75 years is approached with a questionnaire to determine lung cancer risk. Those with an estimated risk of at least 5% of developing lung cancer in the next 5 years (using the Liverpool Lung project risk model) are invited to participate in the trial. Here, we present demographic, risk, and response rate data from the first 88,897 individuals approached. Of note, 23,794 individuals (26.8% of all approached) responded positively to the initial questionnaire; 12% of these were high risk. Higher socioeconomic status correlated positively with response, but inversely with risk (P < 0.001). The 50- to 55-year age group was least likely to participate, and at lowest cancer risk. Only 5% of clinic attendees were ages ≤60 years (compared with 47% of all 88,897 approached); this has implications for cost effectiveness. Among positive responders, there were more ex-smokers than expected from population figures (40% vs. 33%), and fewer current smokers (14% vs. 17.5%). Of note, 32.7% of current smokers and 18.4% of ex-smokers were designated as high risk. Overall, 1,452 of 23,794 positive responders (6.1%) were deemed high risk and attended a recruitment clinic. UKLS is the first LDCT population screening trial, selecting high-risk subjects using a validated individual risk prediction model. Key findings: (i) better recruitment from ex- rather than current smokers, (ii) few clinic attendees ages early 50s, and (iii) representative number of socioeconomically deprived people recruited, despite lower response rates. Cancer Prev Res; 7(3); 362–71. ©2014 AACR.
Data from Microsatellite Instability and DNA Mismatch Repair Protein Deficiency in Lynch Syndrome Colorectal Polyps
Authors: Yurgelun Matthew B. , Goel Ajay , Hornick Jason L. , Sen Ananda , Turgeon Danielle Kim , Ruffin Mack T. , Marcon Norman E. , Baron John A. , Bresalier Robert S. , Syngal Sapna , Brenner Dean E. , Boland C. Richard , Stoffel Elena M.
Published: March 2024

Abstract
Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Our aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in Lynch syndrome–associated polyps. Sixty-two colorectal polyps—37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP)—from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), 1.52–65.65; P = 0.02] and deficient MMR protein expression (OR, 3.17; 95% CI, 1.20–8.37; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR protein expression by immunohistochemistry. Our finding that the prevalence of MMR deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome–associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas. Cancer Prev Res; 5(4); 574–82. ©2012 AACR.
Data from New Directions in Reducing Stress Effects on Cancer
Authors: Melhem-Bertrandt Amal , Sood Anil K.
Published: March 2024

Abstract
A growing body of evidence is now connecting neuroendocrine mediators of the stress response to cancer biology. Al-Wadei and colleagues report a study in this issue of the journal (beginning on page 189) that provides a new piece of this evidence, adding the inhibitory neurotransmitter γ-aminobutyric acid to this intricate pathway. Their mouse model study supports the hypothesis that stress mediators contribute to lung cancer progression and that known inhibitors of the stress pathway might block such effects, thus adding to the impetus for studying cancer prevention strategies targeting the stress pathway. Cancer Prev Res; 5(2); 147–9. ©2012 AACR.
Data from p16INK4a Expression and Breast Cancer Risk in Women with Atypical Hyperplasia
Authors: Radisky Derek C. , Santisteban Marta , Berman Hal K. , Gauthier Mona L. , Frost Marlene H. , Reynolds Carol A. , Vierkant Robert A. , Pankratz V. Shane , Visscher Daniel W. , Tlsty Thea D. , Hartmann Lynn C.
Published: March 2024

Abstract
p16, a nuclear protein encoded by the p16INK4a gene, is a regulator of cell-cycle regulation. Previous studies have shown that expression of p16 in tissue biopsies of patients with ductal carcinoma in situ (DCIS) is associated with increased risk of breast cancer, particularly when considered in combination with other markers such as Ki-67 and COX-2. Here, we evaluated how expression of p16 in breast tissue biopsies of women with atypical hyperplasia (AH), a putative precursor lesion to DCIS, is associated with subsequent development of cancer. p16 expression was assessed by immunohistochemistry in archival sections from 233 women with AH diagnosed at the Mayo Clinic. p16 expression in the atypical lesions was scored by percentage of positive cells and intensity of staining. We also studied coexpression of p16, with Ki-67 and COX-2, biomarkers of progression in AH. Risk factor and follow-up data were obtained via study questionnaire and medical records. Forty-seven patients (20%) developed breast cancer with a median follow-up of 14.5 years. Staining of p16 was increased in older patients relative to younger patients (P = 0.0025). Although risk of developing breast cancer was not associated with increased p16 expression, joint overexpression of Ki-67 and COX-2 was found to convey stronger risk of breast cancer in the first 10 years after diagnosis as compared with one negative marker (P < 0.01). However, the addition of p16 levels did not strengthen this association. p16 overexpression, either alone or in combination with COX-2 and Ki-67, does not significantly stratify breast cancer risk in women with AH. Cancer Prev Res; 4(12); 1953–60. ©2011 AACR.
Data from Dietary Tomato and Lycopene Impact Androgen Signaling- and Carcinogenesis-Related Gene Expression during Early TRAMP Prostate Carcinogenesis
Authors: Wan Lei , Tan Hsueh-Li , Thomas-Ahner Jennifer M. , Pearl Dennis K. , Erdman John W. , Moran Nancy E. , Clinton Steven K.
Published: March 2024

Abstract
Consumption of tomato products containing the carotenoid lycopene is associated with a reduced risk of prostate cancer. To identify gene expression patterns associated with early testosterone-driven prostate carcinogenesis, which are impacted by dietary tomato and lycopene, wild-type (WT) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control or tomato- or lycopene-containing diets from 4 to 10 weeks of age. Eight-week-old mice underwent sham surgery, castration, or castration followed by testosterone repletion (2.5 mg/kg/d initiated 1 week after castration). Ten-week-old intact TRAMP mice exhibit early multifocal prostatic intraepithelial neoplasia. Of the 200 prostate cancer–related genes measured by quantitative NanoString, 189 are detectable, 164 significantly differ by genotype, 179 by testosterone status, and 30 by diet type (P < 0.05). In TRAMP, expression of Birc5, Mki67, Aurkb, Ccnb2, Foxm1, and Ccne2 is greater compared with WT and is decreased by castration. In parallel, castration reduces Ki67-positive staining (P < 0.0001) compared with intact and testosterone-repleted TRAMP mice. Expression of genes involved in androgen metabolism/signaling pathways is reduced by lycopene feeding (Srd5a1) and by tomato feeding (Srd5a2, Pxn, and Srebf1). In addition, tomato feeding significantly reduced expression of genes associated with stem cell features, Aldh1a and Ly6a, whereas lycopene feeding significantly reduced expression of neuroendocrine differentiation–related genes, Ngfr and Syp. Collectively, these studies demonstrate a profile of testosterone-regulated genes associated with early prostate carcinogenesis that are potential mechanistic targets of dietary tomato components. Future studies on androgen signaling/metabolism, stem cell features, and neuroendocrine differentiation pathways may elucidate the mechanisms by which dietary tomato and lycopene impact prostate cancer risk. Cancer Prev Res; 7(12); 1228–39. ©2014 AACR.
Data from Obesity Is Associated with Inflammation and Elevated Aromatase Expression in the Mouse Mammary Gland
Authors: Subbaramaiah Kotha , Howe Louise R. , Bhardwaj Priya , Du Baoheng , Gravaghi Claudia , Yantiss Rhonda K. , Zhou Xi Kathy , Blaho Victoria A. , Hla Timothy , Yang Peiying , Kopelovich Levy , Hudis Clifford A. , Dannenberg Andrew J.
Published: March 2024

Abstract
Elevated circulating estrogen levels are associated with increased risk of breast cancer in obese postmenopausal women. Following menopause, the biosynthesis of estrogens through CYP19 (aromatase)-mediated metabolism of androgen precursors occurs primarily in adipose tissue, and the resulting estrogens are then secreted into the systemic circulation. The potential links between obesity, inflammation, and aromatase expression are unknown. In both dietary and genetic models of obesity, we observed necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS) in the mammary glands and visceral fat. The presence of CLS was associated with activation of NF-κB and increased levels of proinflammatory mediators (TNF-α, IL-1β, Cox-2), which were paralleled by elevated levels of aromatase expression and activity in the mammary gland and visceral fat of obese mice. Analyses of the stromal-vascular and adipocyte fractions of the mammary gland suggested that macrophage-derived proinflammatory mediators induced aromatase and estrogen-dependent gene expression (PR, pS2) in adipocytes. Saturated fatty acids, which have been linked to obesity-related inflammation, stimulated NF-κB activity in macrophages leading to increased levels of TNF-α, IL-1β, and Cox-2, each of which contributed to the induction of aromatase in preadipocytes. The discovery of the obesity → inflammation → aromatase axis in the mammary gland and visceral fat and its association with CLS may provide insight into mechanisms underlying the increased risk of hormone receptor-positive breast cancer in obese postmenopausal women, the reduced efficacy of aromatase inhibitors in the treatment of breast cancer in these women, and their generally worse outcomes. The presence of CLS may be a biomarker of increased breast cancer risk or poor prognosis. Cancer Prev Res; 4(3); 329–46. ©2011 AACR.
Data from The Concentrations of EGFR, LRG1, ITIH4, and F5 in Serum Correlate with the Number of Colonic Adenomas in ApcPirc/+ Rats
Authors: Ivancic Melanie M. , Irving Amy A. , Jonakin Kelli G. , Dove William F. , Sussman Michael R.
Published: March 2024

Abstract
The development of noninvasive methods for early detection of colon cancer is critical for the successful management of this disease. Using a targeted quantitative proteomics technique, we assessed the ability of 12 serum proteins to detect the presence of colonic polyps in the ApcPirc/+ rat model of familial colon cancer. Serum protein candidates were selected from gene transcripts upregulated in colonic tumors of ApcPirc/+ rats and from a prior study of serum proteins differentially expressed in mice carrying intestinal adenomas. Proteins were quantified at early stages of polyp formation in a rat cohort monitored longitudinally by colonoscopy over a period of 75 days. Of the 12 proteins monitored at three distinct time points, seven showed differential expression in at least one time point in the serum from ApcPirc/+ rats compared with wild-type rats. Tumor multiplicity correlated with protein expression changes, and most tumors grew during the study. EGFR, LRG1, ITIH4, and F5 displayed the most robust tumor-associated protein expression changes over time. Receiver operator characteristic analysis using these four proteins resulted in a sensitivity of 100%, a specificity of 80%, and an area under the curve of 0.93 at 135 days of age, when the Pirc rats bore an average of 19 tumors in the colon and seven in the small intestine. The results of this study demonstrate that the quantitative analysis of a panel of serum proteins can detect the presence of early intestinal tumors in a rat model, and provides support for future measurements in humans. Cancer Prev Res; 7(11); 1160–9. ©2014 AACR.
Data from Biological Activity of Celecoxib in the Bronchial Epithelium of Current and Former Smokers
Authors: Kim Edward S. , Hong Waun K. , Lee J. Jack , Mao Li , Morice Rodolfo C. , Liu Diane D. , Jimenez Carlos A. , Eapen Georgie A. , Lotan Reuben , Tang Ximing , Newman Robert A. , Wistuba Ignacio I. , Kurie Jonathan M.
Published: March 2024

Abstract
Non–small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the bronchial epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in bronchial epithelium. No cardiac toxicities were observed in the participants. Although the effect of low-dose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers—a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the bronchial epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non–small cell lung cancer chemoprevention may be warranted. Cancer Prev Res; 3(2); 148–59
Data from Effects of Oral Contraceptives or a Gonadotropin-Releasing Hormone Agonist on Ovarian Carcinogenesis in Genetically Engineered Mice
Authors: Romero Iris L. , Gordon Ilyssa O. , Jagadeeswaran Sujatha , Mui Keeley L. , Lee Woo Seok , Dinulescu Daniela M. , Krausz Thomas N. , Kim Helen H. , Gilliam Melissa L. , Lengyel Ernst
Published: March 2024

Abstract
Although epidemiologic evidence for the ability of combined oral contraception (OC) to reduce the risk of ovarian cancer (OvCa) is convincing, the biological mechanisms underlying this effect are largely unknown. We conducted the present study to determine if OC also influences ovarian carcinogenesis in a genetic mouse model and, if so, to investigate the mechanism underlying the protective effect. LSL-K-rasG12D/+PtenloxP/loxP mice were treated with ethinyl estradiol plus norethindrone, contraceptive hormones commonly used in combined OC, or norethindrone alone, or a gonadotropin-releasing hormone agonist. The combined OC had a 29% reduction in mean total tumor weight compared with placebo (epithelial tumor weight, −80%). Norethindrone alone reduced mean total tumor weight by 42% (epithelial tumor weight, −46%), and the gonadotropin-releasing hormone agonist increased mean total tumor weight by 71% (epithelial tumor weight, +150%). Large variations in tumor size affected the P values for these changes, which were not statistically significant. Nonetheless, the OC reductions are consistent with the epidemiologic data indicating a protective effect of OC. Matrix metalloproteinase-2 activity was decreased in association with OC, indicating that OC may affect ovarian carcinogenesis by decreasing proteolytic activity, an important early event in the pathogenesis of OvCa. In contrast, OC increased invasion in a K-ras/Pten OvCa cell line established from the mouse tumors, suggesting that OC hormones, particularly estrogen, may have a detrimental effect after the disease process is under way. Our study results support further investigation of OC effects and mechanisms for OvCa prevention.
Data from Cancer Prevention Research in China
Authors: Yu Siwang , Yang Chung S. , Li Junyao , You Weicheng , Chen Jianguo , Cao Ya , Dong Zigang , Qiao Youlin
Published: March 2024

Abstract
Although cancer incidence and mortality rates in the United States and some European countries have started to decrease, those in developing countries are increasing. China, the most populous developing country, is facing a serious challenge from cancer. Cancer incidence has been increasing for decades, and cancer is the leading cause of death in China. In 2012, the cancer incidence was 174.0 per 100,000, and the cancer mortality was 122.2 per 100,000 in China. In addition to the still-prevalent traditional Chinese cancers of the stomach, liver, esophagus, cervix, and nasopharynx, the incidence of “Western” cancers such those of the lung, breast, and colorectum has increased alarmingly in recent years. These increases are likely due to the lifestyle and environmental changes associated with rapid economic development and population aging. More importantly, a large portion of these cancers are preventable. Researchers in China have made important contributions to cancer prevention research, especially in the traditional Chinese cancers. More cancer prevention research and measures, especially on the major emerging cancers, are urgently needed. This review article highlights some of the past achievements and present needs in cancer prevention research in China and suggests important areas for future studies. Cancer Prev Res; 8(8); 662–74. ©2015 AACR.
Data from Smoking Is Associated with Acute and Chronic Prostatic Inflammation: Results from the REDUCE Study
Authors: Moreira Daniel M. , Nickel J. Curtis , Gerber Leah , Muller Roberto L. , Andriole Gerald L. , Castro-Santamaria Ramiro , Freedland Stephen J.
Published: March 2024

Abstract
Both anti- and proinflammatory effects of cigarette smoking have been described. As prostate inflammation is common, we hypothesized smoking could contribute to prostate inflammation. Thus, we evaluated the association of smoking status with acute and chronic inflammation within the prostate of men undergoing prostate biopsy. We retrospectively analyzed 8,190 men ages 50 to 75 years with PSA levels between 2.5 and 10 ng/mL enrolled in the Reduction by Dutasteride of Prostate Cancer Events study. Smoking status was self-defined as never, former, or current. Prostate inflammation was assessed by systematic central review blinded to smoking status. The association of smoking with inflammation in the baseline, 2-year, and 4-year biopsies was evaluated with univariable and multivariable logistic regressions. At study enrollment, 1,233 (15%), 3,203 (39%), and 3,754 (46%) men were current, former, and never smokers, respectively. Current smokers were significantly younger and had smaller prostates than former and never smokers (all P < 0.05). Former smokers were significantly heavier than current and never smokers (P < 0.001). Acute and chronic prostate inflammations were identified in 1,261 (15%) and 6,352 (78%) baseline biopsies, respectively. In univariable analysis, current smokers were more likely to have acute inflammation than former (OR, 1.35; P, 0.001) and never smokers (OR, 1.36; P, 0.001). The results were unchanged at 2- and 4-year biopsies. In contrast, current smoking was linked with chronic inflammation in the baseline biopsy, but not at 2- and 4-year biopsies. In conclusion, among men undergoing prostate biopsy, current smoking was independently associated with acute and possibly chronic prostate inflammations. Cancer Prev Res; 8(4); 312–7. ©2015 AACR.
Data from Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Premenopausal Women
Authors: Fabian Carol J. , Kimler Bruce F. , Phillips Teresa A. , Box Jessica A. , Kreutzjans Amy L. , Carlson Susan E. , Hidaka Brandon H. , Metheny Trina , Zalles Carola M. , Mills Gordon B. , Powers Kandy R. , Sullivan Debra K. , Petroff Brian K. , Hensing Whitney L. , Fridley Brooke L. , Hursting Stephen D.
Published: March 2024

Abstract
Higher intakes of the omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) have been variably associated with reduced risk of premenopausal breast cancer. The purpose of this pilot trial was to assess feasibility and explore the effects of high-dose EPA and DHA on blood and benign breast tissue risk biomarkers before design of a placebo-controlled phase IIB trial. Premenopausal women with evidence of hyperplasia ± atypia by baseline random periareolar fine needle aspiration were given 1860 mg of EPA + 1500 mg of DHA ethyl esters daily for 6 months. Blood and benign breast tissue were sampled during the same menstrual cycle phase prestudy and a median of 3 weeks after last dose. Additional blood was obtained within 24 hours of last dose. Feasibility, which was predefined as 50% uptake, 85% retention, and 70% compliance, was demonstrated with 46% uptake, 94% completion, and 85% compliance. Cytologic atypia decreased from 77% to 38% (P = 0.002), and Ki-67 from a median of 2.1% to 1.0% (P = 0.021) with an increase in the ratio of EPA + DHA to AA in erythrocyte phospholipids but no change in blood hormones, adipokines, or cytokines. Exploratory breast proteomics assessment showed decreases in several proteins involved in hormone and cytokine signaling with mixed effects on those in the AKT/mTOR pathways. Further investigation of EPA plus DHA for breast cancer prevention in a placebo-controlled trial in premenopausal women is warranted. Cancer Prev Res; 8(10); 912–21. ©2015 AACR.

See related article, p. 922.
Data from Alu in Lynch Syndrome: A Danger SINE?
Authors: Hitchins Megan P. , Burn John
Published: March 2024

Abstract
Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline loss of a DNA mismatch repair gene. In a significant proportion of cases, loss of function of the MSH2 mismatch repair gene is caused by large heterogeneous deletions involving MSH2 and/or the adjacent EPCAM gene. These deletions usually result from homologous malrecombination events between Alu elements, a family of short interspersed nuclear elements (SINE). Recent recognition that the extent of these deletions influences phenotypic outcome provided new impetus for fine-mapping the breakpoints. In doing so, Pérez-Cabornero and colleagues uncovered new evidence for Alu-mediated ancestral founder deletions within MSH2 in the Spanish Lynch syndrome population (as reported beginning on pages 1546 and 1556 in this issue of the journal). This is the first such finding to date and prompted a revisitation of the role of Alu elements in the causation of Lynch syndrome. Whether Alu density is a danger sign for genomic regions prone to rearrangement and what additional factors may be required to actuate these events remain to be discovered. Cancer Prev Res; 4(10); 1527–30. ©2011 AACR.
Data from Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model
Authors: Chandra Swati , Nymeyer Ariel C. , Rice Photini Faith , Gerner Eugene W. , Barton Jennifer K.
Published: March 2024

Abstract
Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High-resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: (i) daily for 20 weeks (sulindac-daily); (ii) for 2 weeks, then no sulindac for 2 weeks, cycle repeated 5 times (sulindac-2); (iii) for 10 weeks (“on”), then no sulindac for 10 weeks (“off”; sulindac-10); and (iv) no sulindac (sulindac-none). Sulindac-2 and sulindac-daily had statistically significantly lower final tumor counts and slopes (change in number of tumors per week) when compared with sulindac-none (P < 0.0001). All of the treatment groups had statistically significantly lower final tumor burdens and slopes when compared with sulindac-none (P < 0.001). There was a prolonged latency period in the sulindac-10 group, with no significant difference between the “off” portion of this treatment and sulindac-none. These results suggest that, although daily doses of sulindac provide the most optimal effects, intermittent doses of sulindac in a 50% duty cycle with an overall 4-week period (sulindac-2 model) can provide highly effective chemoprevention of colorectal cancer in this model. After cessation of sulindac treatment (sulindac-10 “off”), there is no evidence of either a persistent chemopreventive effect or a rebound effect. Cancer Prev Res; 10(8); 459–66. ©2017 AACR.
Data from Germline and Somatic NF1 Alterations Are Linked to Increased HER2 Expression in Breast Cancer
Authors: Wang Xia , Kallionpää Roope A. , Gonzales Patrick R. , Chitale Dhananjay A. , Tousignant Renee N. , Crowley Jacob P. , Chen Zhihua , Yoder Sean J. , Blakeley Jaishri O. , Acosta Maria T. , Korf Bruce R. , Messiaen Ludwine M. , Tainsky Michael A.
Published: March 2024

Abstract
NF1 germline mutation predisposes to breast cancer. NF1 mutations have also been proposed as oncogenic drivers in sporadic breast cancers. To understand the genomic and histologic characteristics of these breast cancers, we analyzed the tumors with NF1 germline mutations and also examined the genomic and proteomic profiles of unselected tumors. Among 14 breast cancer specimens from 13 women affected with neurofibromatosis type 1 (NF1), 9 samples (NF + BrCa) underwent genomic copy number (CN) and targeted sequencing analysis. Mutations of NF1 were identified in two samples and TP53 were in three. No mutation was detected in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, and STK11. HER2 (ErbB2) overexpression was detected by IHC in 69.2% (9/13) of the tumors. CN gain/amplification of ERBB2 was detected in 4 of 9 with DNA analysis. By evaluating HER2 expression and NF1 alterations in unselected invasive breast cancers in TCGA datasets, we discovered that among samples with ERBB2 CN gain/amplification, the HER2 mRNA and protein expression were much more pronounced in NF1-mutated/deleted samples in comparison with NF1-unaltered samples. This finding suggests a synergistic interplay between these two genes, potentially driving the development of breast cancer harboring NF1 mutation and ERBB2 CN gain/amplification. NF1 gene loss of heterozygosity was observed in 4 of 9 NF + BrCa samples. CDK4 appeared to have more CN gain in NF + BrCa and exhibited increased mRNA expression in TCGA NF1--altered samples. Cancer Prev Res; 11(10); 655–64. ©2018 AACR.
Data from Immune Responses Vary in Preinvasive Colorectal Lesions by Tumor Location and Histology
Authors: Wallace Kristin , El Nahas Georges J. , Bookhout Christine , Thaxton Jessica E. , Lewin David N. , Nikolaishvili-Feinberg Nana , Cohen Stephanie M. , Brazeal J. Grant , Hill Elizabeth G. , Wu Jennifer D. , Baron John A. , Alekseyenko Alexander V.
Published: March 2024

Abstract
Immune responses vary in colorectal cancers, which strongly influence prognosis. However, little is known about the variance in immune response within preinvasive lesions. The study aims to investigate how the immune contexture differs by clinicopathologic features (location, histology, dysplasia) associated with progression and recurrence in early carcinogenesis. We performed a cross-sectional study using preinvasive lesions from the surgical pathology laboratory at the Medical University of South Carolina. We stained the tissues with immunofluorescence antibodies, then scanned and analyzed expression using automated image analysis software. We stained CD117 as a marker of mast cells, CD4/RORC to indicate Th17 cells, MICA/B as a marker of NK-cell ligands, and also used antibodies directed against cytokines IL6, IL17A, and IFNγ. We used negative binomial regression analysis to compare analyte density counts by location, histology, degree of dysplasia adjusted for age, sex, race, and batch. All immune markers studied (except IL17a) had significantly higher density counts in the proximal colon than distal colon and rectum. Increases in villous histology were associated with significant decreases in immune responses for IL6, IL17a, NK ligand, and mast cells. No differences were observed in lesions with low- and high-grade dysplasia, except in mast cells. The lesions of the proximal colon were rich in immune infiltrate, paralleling the responses observed in normal mucosa and invasive disease. The diminishing immune response with increasing villous histology suggests an immunologically suppressive tumor environment. Our findings highlight the heterogeneity of the immune responses in preinvasive lesions, which may have implications for prevention strategies.
Prevention Relevance:
Our study is focused on immune infiltrate expression in preinvasive colorectal lesions; our results suggest important differences by clinicopathologic features that have implications for immune prevention research.
Data from Toll-like Receptor-6 Signaling Prevents Inflammation and Impacts Composition of the Microbiota During Inflammation-Induced Colorectal Cancer
Authors: Kim Jee-Hyun , Kordahi Melissa C. , Chac Denise , DePaolo R. William
Published: March 2024

Abstract
Tightly regulated immune responses must occur in the intestine to avoid unwanted inflammation, which may cause chronic sequela leading to diseases such as colorectal cancer. Toll-like receptors play an important role in preventing aberrant immune responses in the intestine by sensing endogenous commensal microbiota and delivering important regulatory signals to the tissue. However, the role that specific innate receptors may play in the development of chronic inflammation and their impact on the composition of the colonic microbiota is not well understood. Using a model of inflammation-induced colorectal cancer, we found that Lactobacillus species are lost more quickly in wild-type (WT) mice than TLR6-deficient mice resulting in overall differences in bacterial composition. Despite the longer retention of Lactobacillus, the TLR6-deficient mice presented with more tumors and a worse overall outcome. Restoration of the lost Lactobacillus species suppressed inflammation, reduced tumor number, and prevented change in the abundance of Proteobacteria only when given to WT mice, indicating the effect of these Lactobacillus are TLR6 dependent. We found that the TLR6-dependent effects of Lactobacillus could be dissociated from one another via the involvement of IL10, which was necessary to dampen the inflammatory microenvironment, but had no effect on bacterial composition. Altogether, these data suggest that innate immune signals can shape the composition of the microbiota under chronic inflammatory conditions, bias the cytokine milieu of the tissue microenvironment, and influence the response to microbiota-associated therapies.