bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice
Authors: Chang Ya-Fang , Chuang Hui-Yen , Hsu Chien-Hui , Liu Ren-Shyan , Gambhir Sanjiv Sam , Hwang Jeng-Jong
Published: April 2023

Abstract
Adoptive T-cell therapy involves the ex vivo expansion and subsequent transfusion of tumor-specific T lymphocytes to eliminate tumors. Using immune modulators to block immunosuppressive factors in the tumor microenvironment has emerged as a promising strategy to enhance T-cell–mediated tumor regression. Curcumin, a major component of turmeric, has been shown to possess antitumor and immunomodulatory effects by regulating a diverse range of molecular targets. Thus, we hypothesize that these beneficial effects of curcumin may improve the therapeutic efficacy of adoptive therapy. Here, we have shown that curcumin enhances cytotoxicity of CD8+ T cells toward tumors via alteration of the tumor microenvironment when combined with adoptive therapy. We found that T-cell accumulation and function were increased in combined treatment due to the blockade of different immunosuppressors, including TGF-β, indoleamine 2,3-dioxygenase, and regulatory T cells. Furthermore, bioluminescent imaging with a granzyme B promoter–conjugated optical reporter also reflected improved cytotoxicity of antigen-specific CD8+ T cells in tumor-bearing mice during treatment. These findings suggest that combination of multitargeting drugs, such as curcumin, with adoptive therapy may have potential for clinical application. In addition, using a granzyme B–specific imaging reporter to assess T-cell function may also be applied for the development and therapeutic evaluation of new immunotherapy in preclinical studies. Cancer Prev Res; 5(3); 444–52. ©2011 AACR.
Data from Health Benefits and Cost-Effectiveness of Primary Genetic Screening for Lynch Syndrome in the General Population
Authors: Dinh Tuan A. , Rosner Benjamin I. , Atwood James C. , Boland C. Richard , Syngal Sapna , Vasen Hans F. A. , Gruber Stephen B. , Burt Randall W.
Published: April 2023

Abstract
In current clinical practice, genetic testing to detect Lynch syndrome mutations ideally begins with diagnostic testing of an individual affected with cancer before offering predictive testing to at-risk relatives. An alternative strategy that warrants exploration involves screening unaffected individuals via demographic and family histories, and offering genetic testing to those individuals whose risks for carrying a mutation exceed a selected threshold. Whether this approach would improve health outcomes in a manner that is cost-effective relative to current standards of care has yet to be demonstrated. To do so, we developed a simulation framework that integrated models of colorectal and endometrial cancers with a 5-generation family history model to predict health and economic outcomes of 20 primary screening strategies (at a wide range of compliance levels) aimed at detecting individuals with mismatch repair gene mutations and their at-risk relatives. These strategies were characterized by (i) different screening ages for starting risk assessment and (ii) different risk thresholds above which to implement genetic testing. For each strategy, 100,000 simulated individuals, representative of the U.S. population, were followed from the age of 20, and the outcomes were compared with current practice. Findings indicated that risk assessment starting at ages 25, 30, or 35, followed by genetic testing of those with mutation risks exceeding 5%, reduced colorectal and endometrial cancer incidence in mutation carriers by approximately 12.4% and 8.8%, respectively. For a population of 100,000 individuals containing 392 mutation carriers, this strategy increased quality-adjusted life-years (QALY) by approximately 135 with an average cost-effectiveness ratio of $26,000 per QALY. The cost-effectiveness of screening for mismatch repair gene mutations is comparable to that of accepted cancer screening activities in the general population such as colorectal cancer screening, cervical cancer screening, and breast cancer screening. These results suggest that primary screening of individuals for mismatch repair gene mutations, starting with risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost-effective manner relative to current practice. Cancer Prev Res; 4(1): 9–22. ©2010 AACR. Cancer Prev Res; 4(1); 9–22. ©2010 AACR.
Data from Aspirin and Familial Adenomatous Polyposis: Coming Full Circle
Authors: Chan Andrew T.
Published: April 2023

Abstract
This perspective discusses the clinical trial reported by Burn and colleagues in this issue of the journal (beginning on page 655), which assessed aspirin and resistant starch for the prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP). The findings are examined in the context of previous clinical trials of aspirin in patients with sporadic adenomas and of sulindac or celecoxib in patients with FAP. This newly reported work raises important considerations of a role for aspirin in the clinical management of FAP patients and adds to considerations of a role for aspirin in the chemoprevention of colorectal cancer among broader populations. Cancer Prev Res; 4(5); 623–7. ©2011 AACR.
Data from Carcinogen-Induced Skin Tumor Development Requires Leukocytic Expression of the Transcription Factor Runx3
Authors: Bauer Omri , Hantisteanu Shay , Lotem Joseph , Groner Yoram
Published: April 2023

Abstract
Carcinogen-induced skin tumorigenesis depends heavily on proinflammatory tumor-promoting processes. Here, we show that leukocytic Runx3 expression is central to the two-stage DMBA/TPA-induced skin tumorigenesis. Runx3-null mice were highly resistant to this process and concomitant ablation of Runx3 in dendritic and T cells fully recapitulated this resistance. Mechanistically, this resistance was associated with a shift in the skin cytokine milieu toward a tumor nonpermissive microenvironment. Specifically, leukocytic Runx3 loss substantially increased the antitumorigenic cytokine thymic stromal lymphopoietin (TSLP) and profoundly decreased two protumorigenic cytokines, interleukin-17a and osteopontin. Therefore, inflammation-mediated tumor promotion requires leukocytic Runx3 expression, as its loss creates a unique cytokine composition that polarizes the tumor microenvironment to a potent antitumorigenic state. Cancer Prev Res; 7(9); 913–26. ©2014 AACR.
Data from Uterine Serous Carcinoma: Increased Familial Risk for Lynch-Associated Malignancies
Authors: Dewdney Summer B. , Kizer Nora T. , Andaya Abegail A. , Babb Sheri A. , Luo Jingqin , Mutch David G. , Schmidt Amy P. , Brinton Louise A. , Broaddus Russell R. , Ramirez Nilsa C. , Huettner Phyllis C. , McMeekin Donald Scott , Darcy Kathleen , Ali Shamshad , Judson Patricia L. , Mannel Robert S. , Lele Shashikant B. , O'Malley David M. , Goodfellow Paul J.
Published: April 2023

Abstract
Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for patients with serous uterine carcinoma, focusing on Lynch syndrome malignancies. Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair (MMR) abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second-stage analysis was undertaken using data from Gynecologic Oncology Group (GOG)-210. Incidence data for cancers reported in relatives of 348 patients with serous and mixed epithelial and 624 patients with endometrioid carcinoma were compared. Nineteen of 29 (65.5%) patients in the single-institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly overrepresented and a high number of probands (6 of 29, 20.7%) reported pancreatic cancers. None of the probands' tumors had DNA MMR abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case–control study. Pancreatic cancers were, however, significantly more common in relatives of patients with serous cancer [OR, 2.39; 95% confidence interval (CI), 1.06–5.38]. We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of patients with serous cancer in a single-institution study. Follow-up studies suggest that only pancreatic cancers are overrepresented in relatives. DNA MMR defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers. Cancer Prev Res; 5(3); 435–43. ©2012 AACR.
Data from (+)-2-(1-Hydroxyl-4-Oxocyclohexyl) Ethyl Caffeate Suppresses Solar UV-Induced Skin Carcinogenesis by Targeting PI3K, ERK1/2, and p38
Authors: Lim Do Young , Lee Mee-Hyun , Shin Seung Ho , Chen Hanyoung , Ryu Joohyun , Shan Lei , Li Honglin , Bode Ann M. , Zhang Wei-Dong , Dong Zigang
Published: April 2023

Abstract
For decades, skin cancer incidence has increased, mainly because of oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 Cl41 cells without toxicity. PI3K, ERK1/2, and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3K, ERK1/2, and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure. Cancer Prev Res; 7(8); 856–65. ©2014 AACR.
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: April 2023

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 Classifying Patients for Breast Cancer by Detection of Autoantibodies against a Panel of Conformation-Carrying Antigens
Authors: Evans Rick L. , Pottala James V. , Egland Kristi A.
Published: April 2023

Abstract
Patients with breast cancer elicit an autoantibody response against cancer proteins, which reflects and amplifies the cellular changes associated with tumorigenesis. Detection of autoantibodies in plasma may provide a minimally invasive mechanism for early detection of breast cancer. To identify cancer proteins that elicit a humoral response, we generated a cDNA library enriched for breast cancer genes that encode membrane and secreted proteins, which are more likely to induce an antibody response compared with intracellular proteins. To generate conformation-carrying antigens that are efficiently recognized by patients' antibodies, a eukaryotic expression strategy was established. Plasma from 200 patients with breast cancer and 200 age-matched healthy controls were measured for autoantibody activity against 20 different antigens designed to have conformational epitopes using ELISA. A conditional logistic regression model was used to select a combination of autoantibody responses against the 20 different antigens to classify patients with breast cancer from healthy controls. The best combination included ANGPTL4, DKK1, GAL1, MUC1, GFRA1, GRN, and LRRC15; however, autoantibody responses against GFRA1, GRN, and LRRC15 were inversely correlated with breast cancer. When the autoantibody responses against the 7 antigens were added to the base model, including age, BMI, race and current smoking status, the assay had the following diagnostic capabilities: c-stat (95% CI), 0.82 (0.78–0.86); sensitivity, 73%; specificity, 76%; and positive likelihood ratio (95% CI), 3.04 (2.34–3.94). The model was calibrated across risk deciles (Hosmer–Lemeshow, P = 0.13) and performed well in specific subtypes of breast cancer including estrogen receptor positive, HER-2 positive, invasive, in situ and tumor sizes >1 cm. Cancer Prev Res; 7(5); 545–55. ©2014 AACR.
Data from CYLD Inhibits Tumorigenesis and Metastasis by Blocking JNK/AP1 Signaling at Multiple Levels
Authors: de Marval Paula Miliani , Lutfeali Shazia , Jin Jane Y. , Leshin Benjamin , Selim M. Angelica , Zhang Jennifer Y.
Published: April 2023

Abstract
CYLD has been recognized as a tumor suppressor due to its dominant genetic linkage to multiple types of epidermal tumors and a range of other cancers. The molecular mechanisms governing CYLD control of skin cancer are still unclear. Here, we showed that K14-driven epidermal expression of a patient-relevant and catalytically deficient CYLD truncated mutant (CYLDm) sensitized mice to skin tumor development in response to 7,12-dimethylbenz[α]anthracene (DMBA)/(12-O-tetradecanoylphorbol-13-acetate) TPA challenge. Tumors developed on transgenic mice were prone to malignant progression and lymph node metastasis and displayed increased activation of c-Jun-NH2-kinase (JNK) and the downstream c-Jun and c-Fos proteins. Most importantly, topical application of a pharmacologic JNK inhibitor significantly reduced tumor development and abolished metastasis in the transgenic mice. Further in line with these animal data, exogenous expression of CYLDm in A431, a human squamous cell carcinoma (SCC) cell line, markedly enhanced cell growth, migration, and subcutaneous tumor growth in an AP1-depdendent manner. In contrast, expression of the wild-type CYLD inhibited SCC tumorigenesis and AP1 function. Most importantly, CYLDm not only increased JNK activation but also induced an upregulation of K63 ubiquitination on both c-Jun and c-Fos, leading to sustained AP1 activation. Our findings uncovered c-Jun and c-Fos as novel CYLD targets and underscore that CYLD controls epidermal tumorigenesis through blocking the JNK/AP1 signaling pathway at multiple levels. Cancer Prev Res; 4(6); 851–9. ©2011 AACR.
Data from How Do We Safely Get People to Stop Smoking?
Authors: Lam David C.L. , Minna John D.
Published: April 2023

Abstract
Nicotine replacement therapy (NRT) is a valuable, proven, and U.S. Food and Drug Administration–approved tool for smoking cessation. However, the discoveries of functional nicotinic acetylcholine receptors (nAChR) on lung epithelial and cancer cells and of nAChR polymorphisms associated with lung cancer risk, in addition to a large number of preclinical studies indicating that nicotine may promote or facilitate cancer development and growth, have prompted concern that NRT, although important for smoking cessation, may actually augment lung carcinogenesis. Therefore, it is of great public health interest that two independent studies reported in this issue of the journal (Murphy and colleagues, beginning on page 1752, and Maier and colleagues, beginning on page 1743) showed that nicotine given in drinking water at a dose to achieve blood concentrations in mice similar to those achieved in people receiving NRT did not enhance lung carcinogenesis or tumor growth in several mouse models of lung cancer. Effective non-nicotine alternatives to NRT, such as varenicline and bupropion, are also available and perhaps better than NRT for smoking cessation therapy. In the near future, nicotine vaccines will likely be added to the smoking cessation armamentarium. However, the normal and pathophysiologic role of nicotine, nAChRs, and the signaling pathways they activate in lung epithelial cells and lung cancer still requires elucidation. Cancer Prev Res; 4(11); 1724–7. ©2011 AACR.
Data from A New Biomarker That Predicts Colonic Neoplasia Outcome in Patients with Hyperplastic Colonic Polyps
Authors: Do Catherine , Bertrand Claudine , Palasse Julien , Delisle Marie-Bernadette , Shulkes Arthur , Cohen-Jonathan-Moyal Elizabeth , Ferrand Audrey , Seva Catherine
Published: April 2023

Abstract
The most frequently occurring lesions in the colon are the hyperplastic polyps. Hyperplastic polyps have long been considered as lesions with no malignant potential and colonoscopy for these patients is not recommended. However, recent works suggest that hyperplastic polyps may represent precursor lesions of some sporadic colorectal cancers. Until now, no biomarker allows to identify the subset of hyperplastic polyps that may have a malignant potential. Because the hormone precursor progastrin has been involved in colon carcinogenesis, we investigated whether its expression in hyperplastic polyps predicts the occurrence of colonic neoplasm after resection of hyperplastic polyps. We retrospectively analyzed progastrin expression in hyperplastic polyps from 74 patients without history of colorectal pathology. In our study, 41% of patients presenting an initial hyperplastic polyp subsequently developed adenomatous polyps, recognized as precursor lesions for colorectal adenocarcinomas. Progastrin was overexpressed in the hyperplastic polyps in 40% of the patients. We showed a significant association between progastrin overexpression and shortened neoplasm-free survival (P = 0.001). Patients with high overexpression of progastrin had a 5-year neoplasm-free survival rate of 38% as compared with 100% for the patients with low progastrin expression. In addition, we established a predictive test on the basis of progastrin staining and patients' age that predicts occurrence of neoplasm after developing a first hyperplastic polyp with a sensitivity of 100% [95% confidence interval (CI), 79%–100%] and a specificity of 74% (51%–90%). We show that progastrin expression evaluation in hyperplastic polyps is an efficient prognostic tool to determine patients with higher risk of metachronous neoplasms who could benefit from an adapted follow-up. Cancer Prev Res; 5(4); 675–84. ©2012 AACR.
Data from Epigenetic Alteration of DNA in Mucosal Wash Fluid Predicts Invasiveness of Colorectal Tumors
Authors: Kamimae Seiko , Yamamoto Eiichiro , Yamano Hiro-o , Nojima Masanori , Suzuki Hiromu , Ashida Masami , Hatahira Tomo , Sato Akiko , Kimura Tomoaki , Yoshikawa Kenjiro , Harada Taku , Hayashi Seiko , Takamaru Hiroyuki , Maruyama Reo , Kai Masahiro , Nishiwaki Morie , Sugai Tamotsu , Sasaki Yasushi , Tokino Takashi , Shinomura Yasuhisa , Imai Kohzoh , Toyota Minoru
Published: April 2023

Abstract
Although conventional colonoscopy is considered the gold standard for detecting colorectal tumors, accurate staging is often difficult because advanced histology may be present in small colorectal lesions. We collected DNA present in mucosal wash fluid from patients undergoing colonoscopy and then assessed the methylation levels of four genes frequently methylated in colorectal cancers to detect invasive tumors. We found that methylation levels in wash fluid were significantly higher in patients with invasive than those with noninvasive tumors. Cytologic and K-ras mutation analyses suggested that mucosal wash fluid from invasive tumors contained greater numbers of tumor cells than wash fluid from noninvasive tumors. Among the four genes, levels of mir-34b/c methylation had the greatest correlation with the invasion and showed the largest area under the receiver operating characteristic curve (AUC = 0.796). Using cutoff points of mir-34b/c methylation determined by efficiency considerations, the sensitivity/specificity were 0.861/0.657 for the 13.0% (high sensitivity) and 0.765/0.833 for the 17.8% (well-balanced) cutoffs. In the validation test set, the AUC was also very high (0.915), the sensitivity/specificity were 0.870/0.875 for 13.0% and 0.565/0.958 for 17.8%. Using the diagnostic tree constructed by an objective algorithm, the diagnostic accuracy of the invasiveness of colorectal cancer was 91.3% for the training set and 85.1% for the test set. Our results suggest that analysis of the methylation of DNA in mucosal wash fluid may be a good molecular marker for predicting the invasiveness of colorectal tumors. Cancer Prev Res; 4(5); 674–83. ©2011 AACR.
Data from Alveolar Hypoxia Promotes Murine Lung Tumor Growth through a VEGFR-2/EGFR-Dependent Mechanism
Authors: Karoor Vijaya , Le Mysan , Merrick Daniel , Fagan Karen A. , Dempsey Edward C. , Miller York E.
Published: April 2023

Abstract
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD. Cancer Prev Res; 5(8); 1061–71. ©2012 AACR.
Data from The CDK4/6 Inhibitor PD0332991 Reverses Epithelial Dysplasia Associated with Abnormal Activation of the Cyclin-CDK-Rb Pathway
Authors: Cabrera M. Carla , Díaz-Cruz Edgar S. , Kallakury Bhaskar V.S. , Pishvaian Michael J. , Grubbs Clinton J. , Muccio Donald D. , Furth Priscilla A.
Published: April 2023

Abstract
Loss of normal growth control is a hallmark of cancer progression. Therefore, understanding the early mechanisms of normal growth regulation and the changes that occur during preneoplasia may provide insights of both diagnostic and therapeutic importance. Models of dysplasia that help elucidate the mechanisms responsible for disease progression are useful in highlighting potential targets for prevention. An important strategy in cancer prevention treatment programs is to reduce hyperplasia and dysplasia. This study identified abnormal upregulation of cell cycle–related proteins cyclin D1, cyclin-dependent kinase (CDK)4, CDK6, and phosphorylated retinoblastoma protein (pRb) as mechanisms responsible for maintenance of hyperplasia and dysplasia following downregulation of the initiating viral oncoprotein Simian virus 40 (SV40) T antigen. Significantly, p53 was not required for successful reversal of hyperplasia and dysplasia. Ligand-induced activation of retinoid X receptor and PPARγ agonists attenuated cyclin D1 and CDK6 but not CDK4 or phosphorylated pRb upregulation with limited reversal of hyperplasia and dysplasia. PD0332991, an orally available CDK4/6 inhibitor, was able to prevent upregulation of cyclin D1 and CDK6 as well as CDK4 and phosphorylated pRb and this correlated with a more profound reversal of hyperplasia and dysplasia. In summary, the study distinguished CDK4 and phosphorylated pRb as targets for chemoprevention regimens targeting reversal of hyperplasia and dysplasia. Cancer Prev Res; 5(6); 810–21. ©2012 AACR.
Data from Inhibition of mTOR Suppresses UVB-Induced Keratinocyte Proliferation and Survival
Authors: Carr Theresa D. , DiGiovanni John , Lynch Christopher J. , Shantz Lisa M.
Published: April 2023

Abstract
UV radiation is the major risk factor for developing skin cancer, the most prevalent cancer worldwide. Several studies indicate that mTOR signaling is activated by UVB and may play an important role in skin tumorigenesis. mTOR exists in two functionally and compositionally distinct protein complexes: the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-resistant mTOR complex 2 (mTORC2). The purpose of these studies was to investigate the roles of the two mTOR complexes in UVB-mediated proliferation and apoptosis in the skin. We used rapamycin, a pharmacologic inhibitor of mTORC1, and an inducible mTOR-deficient (K5-CreERT2;mTORfl/fl) mouse model that allows epidermal-specific disruption of mTOR following topical treatment with 4-hydroxytamoxifen (4OHT). Rapamycin blocked UVB-induced phosphorylation of S6K, the downstream target of mTORC1, and significantly reduced UVB-stimulated epidermal proliferation and cell-cycle progression, but had no effect on cell death. In contrast, mTOR deletion, which attenuated UVB-induced phosphorylation of both S6K and the mTORC2 target AKTSer473, significantly increased apoptosis both in vivo and in keratinocyte cultures, in addition to reducing hyperproliferation following UVB irradiation. The role of mTORC2 in UVB-induced prosurvival signaling was verified in Rictor−/− mouse embryo fibroblasts, which lack functional mTORC2 and were more sensitive to UVB-induced apoptosis than controls. These studies show that mTORC1 and mTORC2 play unique but complementary roles in controlling proliferation and apoptosis in the skin. Our findings underscore the importance of both mTOR complexes in mediating UVB-induced signaling in keratinocytes and provide new insight into the pathogenesis of skin cancer. Cancer Prev Res; 5(12); 1394–404. ©2012 AACR.
Data from A Randomized, Placebo-Controlled, Preoperative Trial of Allopurinol in Subjects with Colorectal Adenoma
Authors: Puntoni Matteo , Branchi Daniela , Argusti Alessandra , Zanardi Silvia , Crosta Cristiano , Meroni Emanuele , Munizzi Francesco , Michetti Paolo , Coccia Gianni , De Roberto Giuseppe , Bandelloni Roberto , Turbino Laura , Minetti Egle , Mori Marco , Salvi Sandra , Boccardo Simona , Gatteschi Beatrice , Benelli Roberto , Sonzogni Angelica , DeCensi Andrea
Published: April 2023

Abstract
Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis.

After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, β-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue.

Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas β-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of −10.6%, 95% confidence interval (CI), −20.5 to −0.7, and −8.1%, 95% CI, −22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (−16.4%; 95% CI, −29.0 to −3.8). No dose–response relationship was noted, except for NF-κB expression in normal tissue.

Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity. Cancer Prev Res; 6(2); 74–81. ©2012 AACR.
Data from Unfolded Protein Response Signaling and MAP Kinase Pathways Underlie Pathogenesis of Arsenic-Induced Cutaneous Inflammation
Authors: Li Changzhao , Xu Jianmin , Li Fugui , Chaudhary Sandeep C. , Weng Zhiping , Wen Jianming , Elmets Craig A. , Ahsan Habibul , Athar Mohammad
Published: April 2023

Abstract
Arsenic exposure through drinking water is a major global public health problem and is associated with an enhanced risk of various cancers including skin cancer. In human skin, arsenic induces precancerous melanosis and keratosis, which may progress to basal cell and squamous cell carcinoma. However, the mechanism by which these pathophysiologic alterations occur remains elusive. In this study, we showed that subchronic arsenic exposure to SKH-1 mice induced unfolded protein response (UPR) signaling regulated by proteins, inositol-requiring enzyme-1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6). Arsenic activated all three UPR regulatory proteins in the skin. Arsenic induced IRE1 phosphorylation which resulted in augmented splicing of X-box binding protein 1 (XBP-1) leading to its migration to the nucleus, and also enhanced transcriptional activation of downstream target proteins. Hyperphosphorylation of PERK which induces eukaryotic translation initial factor 2α (eIF2α) in a phosphorylation-dependent manner enhanced translation of ATF4, in addition to augmenting proteolytic activation of ATF6 in arsenic-treated skin. A similar increase in the expression of CHOP was observed. Enhanced XBP-1s, ATF4, and ATF6 regulated downstream chaperones GRP94 and GRP78. In addition, arsenic induced inflammation-related p38/MAPKAPK-2 MAPK signaling and alterations in Th-1/Th-2/Th-17 cytokines/chemokines and their receptors. Antioxidant N-acetyl cysteine blocked arsenic-induced reactive oxygen species, with a concomitant attenuation of UPR and mitogen-activated protein kinase (MAPK) signaling and proinflammatory cytokine/chemokine signatures. Our results identify novel pathways involved in the pathogenesis of arsenic-med iated cutaneous inflammation which may also be related to enhanced cancer risk in arsenic exposed cohorts. Cancer Prev Res; 4(12); 2101–9. ©2011 AACR.
Data from Chemoprevention of B-Cell Lymphomas by Inhibition of the Myc Target Spermidine Synthase
Authors: Forshell TachaZi Plym , Rimpi Sara , Nilsson Jonas A.
Published: April 2023

Abstract
The oncogenic transcription factor c-Myc (Myc) is frequently overexpressed in human cancers. Myc is known to induce or repress a large set of genes involved in cell growth and proliferation, explaining the selection for mutations in cancer that deregulate Myc expression. Inhibition of ornithine decarboxylase, an enzyme of the polyamine biosynthetic pathway and a Myc target, has been shown to be chemopreventive. In the present study, we have dissected the role of another enzyme in the polyamine biosynthetic pathway, spermidine synthase (Srm), in Myc-induced cancer. We find that Srm is encoded by a Myc target gene containing perfect E-boxes and that it is induced by Myc in a direct manner. RNA interference against Srm shows that it is important for Myc-induced proliferation of mouse fibroblasts but to a lesser extent for transformation. Using the compound trans-4-methylcyclohexylamine, we show that Srm inhibition can delay the onset of B-cell lymphoma development in λ-Myc transgenic mice. We therefore suggest that inhibition of Srm is an additional chemopreventive strategy that warrants further consideration. Cancer Prev Res; 3(2); 140–7
Data from Obesity, Endogenous Hormone Metabolism, and Prostate Cancer Risk: A Conundrum of “Highs” and “Lows”
Authors: Kaaks Rudolf , Stattin Pär
Published: April 2023

Abstract
This perspective on the report by Neuhouser et al. (beginning on page 279 in this issue of the journal) examines the associations that have been observed between body mass index, serum insulin, preexisting diabetes, androgen metabolism, and prostate cancer risk. Based on data of the Prostate Cancer Prevention Trial, the observations by Neuhouser et al. plus findings from other studies suggest a complex mix of higher and lower risks for high- and low-grade cancer in association with obesity and endogenous hormone metabolism. Cancer Prev Res; 3(3); 259–62
Data from Inhibition of Lung Tumorigenesis by Metformin Is Associated with Decreased Plasma IGF-I and Diminished Receptor Tyrosine Kinase Signaling
Authors: Quinn Brendan J. , Dallos Matthew , Kitagawa Hiroshi , Kunnumakkara Ajaikumar B. , Memmott Regan M. , Hollander M. Christine , Gills Joell J. , Dennis Phillip A.
Published: April 2023

Abstract
Metformin is the most commonly prescribed drug for type II diabetes and is associated with decreased cancer risk. Previously, we showed that metformin prevented tobacco carcinogen (NNK)–induced lung tumorigenesis in a non-diabetic mouse model, which was associated with decreased IGF-I/insulin receptor signaling but not activation of AMPK in lung tissues, as well as decreased circulating levels of IGF-I and insulin. Here, we used liver IGF-I–deficient (LID) mice to determine the importance of IGF-I in NNK-induced lung tumorigenesis and chemoprevention by metformin. LID mice had decreased lung tumor multiplicity and burden compared with wild-type (WT) mice. Metformin further decreased lung tumorigenesis in LID mice without affecting IGF-I levels, suggesting that metformin can act through IGF-I–independent mechanisms. In lung tissues, metformin decreased phosphorylation of multiple receptor tyrosine kinases (RTK) as well as levels of GTP-bound Ras independently of AMPK. Metformin also diminished plasma levels of several cognate ligands for these RTKs. Tissue distribution studies using [14C]-metformin showed that uptake of metformin was high in liver but four-fold lower in lungs, suggesting that the suppression of RTK activation by metformin occurs predominantly via systemic, indirect effects. Systemic inhibition of circulating growth factors and local RTK signaling are new AMPK-independent mechanisms of action of metformin that could underlie its ability to prevent tobacco carcinogen–induced lung tumorigenesis. Cancer Prev Res; 6(8); 801–10. ©2013 AACR.
Data from Parity-Induced Decrease in Systemic Growth Hormone Alters Mammary Gland Signaling: A Potential Role in Pregnancy Protection from Breast Cancer
Authors: Dearth Robert K. , Delgado David A. , Hiney Jill K. , Pathiraja Thushangi , Oesterreich Steffi , Medina Dan , Dees W. Les , Lee Adrian V.
Published: April 2023

Abstract
Early full-term pregnancy is an effective natural protection against breast cancer in both humans and experimental rodents. The protective effect of an early pregnancy is, in part, linked to changes in circulating hormones that are involved in both normal breast development and breast cancer. For example, a reduction in circulating growth hormone (GH) has been shown to protect rats from carcinogen-induced mammary tumors. We examined the ability of a full-term pregnancy to alter the endocrine GH/insulin-like growth factor-I (IGF-I) axis and how this change affected normal mammary gland function in two commonly used rat models (Sprague-Dawley and Wistar Furth). Circulating GH and IGF-I were measured in blood drawn every 30 minutes from parous and age-matched virgin female rats. Mean serum GH levels were significantly decreased (P < 0.01) in parous compared with age-matched virgin rats for both strains. Changes in GH levels were independent of estrous cycle, indicated by a significant (P < 0.05) reduction in circulating levels of GH during estrus and diestrus in both parous strains. Despite the decrease in circulating GH, pituitary GH mRNA levels were unaltered in parous rats. Circulating IGF-I and hepatic IGF-I mRNA were also unaltered by parity in either rat strain. Immunoblot analysis of mammary glands showed decreases in phosphorylation of signal transducer and activator of transcription 5A and Janus-activated kinase 2, suggesting reduced action of GH in the mammary gland. Therefore, although the parity reduction in circulating GH does not affect circulating IGF-I levels, it is possible that reduced GH acts directly at the mammary gland and may play a role in pregnancy protection from breast cancer. Cancer Prev Res; 3(3); 312–21
Data from Lung Cancer Chemoprevention with Celecoxib in Former Smokers
Authors: Mao Jenny T. , Roth Michael D. , Fishbein Michael C. , Aberle Denise R. , Zhang Zuo-Feng , Rao Jian Yu , Tashkin Donald P. , Goodglick Lee , Holmes E. Carmack , Cameron Robert B. , Dubinett Steven M. , Elashoff Robert , Szabo Eva , Elashoff David
Published: April 2023

Abstract
Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2–selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥ 45, ≥ 30 pack-years of smoking, ≥ 1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI) after 6 months of treatment. Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t test). In participants who crossed over to the other study arm at 6 months (all of whom had received 6 months of celecoxib at the end of a 12 months treatment period), the decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in bronchoalveolar lavage (BAL) samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in BAL cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease. Cancer Prev Res; 4(7); 984–93. ©2011 AACR.
Data from Gene Expression Patterns in the Human Breast after Pregnancy
Authors: Asztalos Szilard , Gann Peter H. , Hayes Meghan K. , Nonn Larisa , Beam Craig A. , Dai Yang , Wiley Elizabeth L. , Tonetti Debra A.
Published: April 2023

Abstract
Epidemiologic studies have established that pregnancy has a bidirectional, time-dependent effect on breast cancer risk; a period of elevated risk is followed by a long-term period of protection. The purpose of the present study was to determine whether pregnancy and involution are associated with gene expression changes in the normal breast, and whether such changes are transient or persistent. We examined the expression of a customized gene set in normal breast tissue from nulliparous, recently pregnant (0-2 years since pregnancy), and distantly pregnant (5-10 years since pregnancy) age-matched premenopausal women. This gene set included breast cancer biomarkers and genes related to immune/inflammation, extracellular matrix remodeling, angiogenesis, and hormone signaling. Laser capture microdissection and RNA extraction were done from formalin-fixed paraffin-embedded reduction mammoplasty and benign biopsy specimens and analyzed using real-time PCR arrays containing 59 pathway-specific and 5 housekeeping genes. We report 14 of 64 (22%) of the selected gene set to be differentially regulated (at P < 0.05 level) in nulliparous versus parous breast tissues. Based on gene set analysis, inflammation-associated genes were significantly upregulated as a group in both parous groups compared with nulliparous women (P = 0.03). Moreover, parous subjects had significantly reduced expression of estrogen receptor α (ERα, ESR1), progesterone receptor (PGR), and ERBB2 (Her2/neu) and 2-fold higher estrogen receptor-β (ESR2) expression compared with nulliparous subjects. These initial data, among the first on gene expression in samples of normal human breast, provide intriguing clues about the mechanisms behind the time-dependent effects of pregnancy on breast cancer risk. Cancer Prev Res; 3(3); 301–11
Data from Targeting Epigenetics for Cancer Prevention By Dietary Cancer Preventive Compounds—The Case of miRNA
Authors: Kong Ah-Ng Tony , Zhang Chengyue , Su Zheng-Yuan
Published: April 2023

Abstract
In cancer, genetic mutations have long been considered to be the only driver of neoplasia. However, there is increasing evidence that epigenetic alterations could also play a major role in carcinogenesis and cancer. A number of experimental and epidemiologic studies have shown that many classes of dietary phytochemicals possess cancer-preventive and epigenetic-modifying properties. The report by Derry and colleagues in this issue of the journal shows that grape seed extract (GSE) prevents azoxymethane (AOM)-induced colon colitis via epigenetic microRNA (miRNA) regulation. Although the precise mechanism underlying the control of miRNA expression is not well understood currently, epigenetic changes could play a major role. This report, along with increasing evidence showing the impact of dietary phytochemicals on epigenetic activities, offers new perspectives on miRNA and epigenetic regulation in cancer prevention. Cancer Prev Res; 6(7); 622–4. ©2013 AACR.
Data from Prospective Multicenter Randomized Intermediate Biomarker Study of Oral Contraceptive versus Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome
Authors: Lu Karen H. , Loose David S. , Yates Melinda S. , Nogueras-Gonzalez Graciela M. , Munsell Mark F. , Chen Lee-may , Lynch Henry , Cornelison Terri , Boyd-Rogers Stephanie , Rubin Mary , Daniels Molly S. , Conrad Peggy , Milbourne Andrea , Gershenson David M. , Broaddus Russell R.
Published: April 2023

Abstract
Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population. Cancer Prev Res; 6(8); 774–81. ©2013 AACR.
Data from Concordant DNA Methylation in Synchronous Colorectal Carcinomas
Authors: Konishi Kazuo , Shen Lanlan , Jelinek Jaroslav , Watanabe Yoshiyuki , Ahmed Saira , Kaneko Kazuhiro , Kogo Mari , Takano Toshihumi , Imawari Michio , Hamilton Stanley R. , Issa Jean-Pierre J.
Published: April 2023

Abstract
Epigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P < 0.05). We found significant (P < 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account.