bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Associations between Preserved Foods and Breast Cancer Risk in Hong Kong Chinese Women
Authors: Lee Priscilla Ming Yi , Kwok Chi-Hei , Tsoi Yee-Kei , Wu Cherry , Law Sze-Hong , Tsang Koon-Ho , Yeung Yiu-Cheong , Chan W.C. , Tse Gary M. , Yuen Karen Ka-Wan , Hung Ray Ka Wai , Wang Feng , Tse Lap Ah
Published: March 2024

Abstract
Preserved food such as cured foods may contain nitrate and nitrite that may contribute to the breast cancer development. Evidence on the associations between these preserved food intakes and risk of breast cancer is sparse. This study aimed to examine the associations between preserved foods (i.e., cured meat, pickled vegetables, canned meat, and canned fruit/vegetables) and breast cancer risk in Hong Kong Chinese women. A total of 1,307 breast cancer cases and 1,050 age-matched controls were recruited from three hospitals during November 2011 through January 2018. We used a standardized questionnaire to collect information on dietary factors, including preserved foods. Unconditional multiple logistic regression was performed to calculate the adjusted odds ratio (AOR) of breast cancer in relation to preserved food with adjustment of potential confounders. We further performed stratified analysis according to the breast cancer biology subtypes. We found that cured meat consumption was significantly associated with the risk of breast cancer [AOR, 1.32; 95% confidence interval 95% (CI), 1.06–1.64]. Compared with no cured meat consumption, cured meat intake ≥ once per week was associated with an AOR of 2.66 (95% CI, 1.38–5.35). Women with canned fruit/vegetable ≥ consumption once per week had a higher risk of breast cancer (OR, 1.19; 95% CI, 1.00–1.41), particularly for the HER2-positive subtypes, but it became borderline after adjustment of confounders. Our study reveals a positive association between consumption of cured meat and breast cancer risk in Chinese population. Cured meat intake might be a potential novel risk factor for breast cancer but this would have to be confirmed by large prospective cohort studies.
Prevention Relevance:
The main finding of this case–control study, an association between cured meat intake and a higher risk of breast cancer in Hong Kong Chinese women, contributes to the growing evidence for population-level health benefits of reducing cured meat consumption.
Data from Comparison of Performance Between a Short Categorized Lifestyle Exposure-based Colon Cancer Risk Prediction Tool and a Model Using Continuous Measures
Authors: Liu Ying , Colditz Graham A. , Rosner Bernard A. , Dart Hank , Wei Esther , Waters Erika A.
Published: March 2024

Abstract
Risk prediction models that estimate an individual's risk of developing colon cancer could be used for a variety of clinical and public health interventions, including offering high-risk individuals enhanced screening or lifestyle interventions. However, if risk prediction models are to be translated into actual clinical and public health practice, they must not only be valid and reliable, but also be easy to use. One way of accomplishing this might be to simplify the information that users of risk prediction tools have to enter, but it is critical to ensure no resulting detrimental effects on model performance. We compared the performance of a simplified, largely categorized exposure-based colon cancer risk model against a more complex, largely continuous exposure-based risk model using two prospective cohorts. Using data from the Nurses’ Health Study and the Health Professionals Follow-up Study we included 816 incident colon cancer cases in women and 412 in men. The discrimination of models was not significantly different comparing a categorized risk prediction model with a continuous prediction model in women (c-statistic 0.600 vs. 0.609, Pdiff = 0.07) and men (c-statistic 0.622 vs. 0.618, Pdiff = 0.60). Both models had good calibration in men [observed case count/expected case count (O/E) = 1.05, P > 0.05] but not in women (O/E = 1.19, P < 0.01). Risk reclassification was slightly improved using categorized predictors in men [net reclassification index (NRI) = 0.041] and slightly worsened in women (NRI = −0.065). Categorical assessment of predictor variables may facilitate use of risk assessment tools in the general population without significant loss of performance.
Data from Randomized Controlled Trial of the Gastrin/CCK2 Receptor Antagonist Netazepide in Patients with Barrett's Esophagus
Authors: Abrams Julian A. , Del Portillo Armando , Hills Caitlin , Compres Griselda , Friedman Richard A. , Cheng Bin , Poneros John , Lightdale Charles J. , De La Rue Rachel , di Pietro Massimiliano , Fitzgerald Rebecca C. , Sepulveda Antonia , Wang Timothy C.
Published: March 2024

Abstract
Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm2, SD 620.7; placebo: +307.8 Ki67+ cells/mm2, SD 640.3; P = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype (TFF2, MUC5B) and certain cancer-associated markers (REG3A, PAX9, MUC1), and decreased expression of intestinal markers MUC2, FABP1, FABP2, and CDX1. No serious adverse events related to study drug occurred. The gastrin/CCK2 receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus.

Prevention Relevance: Treatment of patients with Barrett's esophagus with a gastrin/CCK2 receptor antagonist did not have obvious chemopreventive effects.
Data from Identification of a Human Airway Epithelial Cell Subpopulation with Altered Biophysical, Molecular, and Metastatic Properties
Authors: Pagano Paul C. , Tran Linh M. , Bendris Nawal , O'Byrne Sean , Tse Henry T. , Sharma Shivani , Hoech Jonathan W. , Park Stacy J. , Liclican Elvira L. , Jing Zhe , Li Rui , Krysan Kostyantyn , Paul Manash K. , Fontebasso Yari , Larsen Jill E. , Hakimi Shaina , Seki Atsuko , Fishbein Michael C. , Gimzewski James K. , Carlo Dino Di , Minna John D. , Walser Tonya C. , Dubinett Steven M.
Published: March 2024

Abstract
Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the unselected immortalized epithelial cell lines. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8 weeks after selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short-term assays and enhanced outgrowth of premalignant lesions in longer-term assays, thus overcoming important aspects of “metastatic inefficiency.” Overall, our findings indicate that among immortalized premalignant airway epithelial cell lines, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior. Cancer Prev Res; 10(9); 514–24. ©2017 AACR.

See related editorial by Hynds and Janes, p. 491
Data from Effects of Black Raspberry Extract and Protocatechuic Acid on Carcinogen-DNA Adducts and Mutagenesis, and Oxidative Stress in Rat and Human Oral Cells
Authors: Guttenplan Joseph B. , Chen Kun-Ming , Sun Yuan-Wan , Kosinska Wieslawa , Zhou Ying , Kim Seungjin (Agatha) , Sung Youngjae , Gowda Krishne , Amin Shantu , Stoner Gary D. , El-Bayoumy Karam
Published: March 2024

Abstract
Effects of black raspberry (BRB) extract and protocatechuic acid (PCA) on DNA adduct formation and mutagenesis induced by metabolites of dibenzo[a,l]pyrene (DBP) were investigated in rat oral fibroblasts. The DBP metabolites, (±)-anti-11,12-dihydroxy-11,12,-dihydrodibenzo[a,l]pyrene (DBP-diol) and 11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DBPDE) induced dose-dependent DNA adducts and mutations. DBPDE was considerably more potent, whereas the parent compound had no significant effect. Treatment with BRB extract (BRBE) and PCA resulted in reduced DBP-derived DNA adduct levels and reduced mutagenesis induced by DBP-diol, but only BRBE was similarly effective against (DBPDE). BRBE did not directly inactivate DBPDE, but rather induced a cellular response—enhanced DNA repair. When BRBE was added to cells 1 day after the DBP-diol, the BRBE greatly enhanced removal of DBP-derived DNA adducts. As oxidative stress can contribute to several stages of carcinogenesis, BRBE and PCA were investigated for their abilities to reduce oxidative stress in a human leukoplakia cell line by monitoring the redox indicator, 2′,7′-dichlorodihydrofluorescein diacetate (H2DCF) in cellular and acellular systems. BRBE effectively inhibited the oxidation, but PCA was only minimally effective against H2DCF. These results taken together provide evidence that BRBE and PCA can inhibit initiation of carcinogenesis by polycyclic aromatic hydrocarbons; and in addition, BRBE reduces oxidative stress. Cancer Prev Res; 9(8); 704–12. ©2016 AACR.
Data from Plasma 25-Hydroxyvitamin D, Vitamin D Binding Protein, and Risk of Colorectal Cancer in the Nurses' Health Study
Authors: Song Mingyang , Konijeti Gauree Gupta , Yuan Chen , Ananthakrishnan Ashwin N. , Ogino Shuji , Fuchs Charles S. , Giovannucci Edward L. , Ng Kimmie , Chan Andrew T.
Published: March 2024

Abstract
Total circulating 25-hydroxyvitamin D [25(OH)D)] has been associated with lower risk of colorectal cancer. The physiologic mechanism, however, may be more directly related to the free or bioavailable fraction of 25(OH)D, which is influenced by levels of vitamin D binding protein (VDBP). We assessed the association of prediagnosis total, free, and bioavailable 25(OH)D and VDBP with colorectal cancer risk among predominantly white women in the Nurses' Health Study (NHS) who provided a blood specimen in 1989–1990. We documented 378 cases of colorectal cancer through 2011 and matched them to 689 controls according to age and time of blood draw. We genotyped two common polymorphisms in the gene coding VDBP and calculated free and bioavailable 25(OH)D levels based on total 25(OH)D, VDBP, albumin, and their estimated genotype-specific binding affinities. Total 25(OH)D was associated with lower colorectal cancer risk (P for trend = 0.01). Compared with women in the lowest quintile of total 25(OH)D, those in the highest quintile had a multivariable-adjusted odds ratio (OR) for colorectal cancer of 0.54 [95% confidence interval (CI), 0.33–0.87]. Comparing extreme quintiles, we did not find any significant association with risk of colorectal cancer for VDBP (OR, 0.98; 95% CI, 0.65–1.47), free 25(OH)D (OR, 0.71; 95% CI, 0.46–1.10), or bioavailable 25(OH)D (OR, 0.92; 95% CI, 0.60–1.42). In conclusion, prediagnosis levels of total, but not free or bioavailable 25(OH)D, were associated with lower colorectal cancer risk. Although our findings support an inverse association of vitamin D with colorectal cancer, this association does not appear to be due to the unbound or bioavailable fraction of circulating vitamin D. Cancer Prev Res; 9(8); 664–72. ©2016 AACR.
Data from A Multistage Murine Breast Cancer Model Reveals Long-Lived Premalignant Clones Refractory to Parity-Induced Protection
Authors: Li Shuo , Gestl Shelley A. , Gunther Edward J.
Published: March 2024

Abstract
Breast cancers evolve in a multistage process that can span decades after a carcinogenic exposure. It follows that long-lived precursor breast lesions persist in a subclinical state prior to completing malignant transformation, yet widely used breast cancer models lack an experimental framework for targeting premalignant disease. Inspired by classic multistage skin carcinogenesis protocols, we combined chemical carcinogenesis with transgenic mouse modeling to resolve mouse mammary carcinogenesis into discrete initiation and progression stages. At the initiation stage, exposure to the carcinogen 7,12-dimethylbenzanthracene (DMBA) generated “initiated mammary epithelial cells” (iMEC) by introducing a stereotyped HrasQ61L driver mutation. Whether DMBA exposure occurred during puberty or adulthood, mice efficiently acquired iMEC clones that eluded detection by conventional histology, yet were long lived, persisting in a clinically silent state for months in the absence of a cooperating event. At the progression stage, inducible activation of oncogenic Wnt signaling drove rapid and synchronous transformation of latent iMECs into overt mammary carcinomas, while Wnt activation in neighboring normal mammary epithelium yielded only benign hyperplasia over this same time period. Although early parity (completion of a full-term pregnancy) reduces breast cancer risk in some contexts, standard parity-induced protection schemes failed to eliminate iMECs in our multistage model, suggesting Wnt-responsive iMECs are maintained by hormone-independent mechanisms. Variations on our multistage modeling strategy may help to identify and validate cellular and molecular targets for breast cancer chemoprevention.
Data from Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate
Authors: Zumwalde Nicholas A. , Haag Jill D. , Sharma Deepak , Mirrielees Jennifer A. , Wilke Lee G. , Gould Michael N. , Gumperz Jenny E.
Published: March 2024

Abstract
Developing strategies to enhance cancer prevention is a paramount goal, particularly given recent concerns about surgical treatment of preinvasive states such as ductal carcinoma in situ. Promoting effective immunosurveillance by leukocytes that scan for nascent neoplastic transformations represents a potential means to achieve this goal. Because most breast cancers arise within the ductal epithelium, enhancing protective immunosurveillance will likely necessitate targeting one or more of the distinctive lymphocyte types found in these sites under normal conditions. Here, we have characterized the intraepithelial lymphocyte compartment of non-cancerous human breast tissue and identified a subset of T lymphocytes that can be pharmacologically targeted to enhance their responses to breast cancer cells. Specifically, Vδ2+ γδ T cells were consistently present in preparations of mammary ductal epithelial organoids and they proliferated in response to zoledronic acid, an aminobisphosphonate drug. Vδ2+ T cells from breast ductal organoids produced the antitumor cytokine IFNγ and efficiently killed bisphosphonate-pulsed breast carcinoma cells. These findings demonstrate the potential for exploiting the ability of Vδ2+ γδ T cells to respond to FDA-approved bisphosphonate drugs as a novel immunotherapeutic approach to inhibit the outgrowth of breast cancers. Cancer Prev Res; 9(4); 305–16. ©2016 AACR.
Data from The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers
Authors: Wang Yi , Narayanapillai Sreekanth C. , Tessier Katelyn M. , Strayer Lori G. , Upadhyaya Pramod , Hu Qi , Kingston Rick , Salloum Ramzi G. , Lu Junxuan , Hecht Stephen S. , Hatsukami Dorothy K. , Fujioka Naomi , Xing Chengguo
Published: March 2024

Abstract
Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.
Data from High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer
Authors: Bannon Sarah A. , Montiel Maria F. , Goldstein Jennifer B. , Dong Wenli , Mork Maureen E. , Borras Ester , Hasanov Merve , Varadhachary Gauri R. , Maitra Anirban , Katz Matthew H. , Feng Lei , Futreal Andrew , Fogelman David R. , Vilar Eduardo , McAllister Florencia
Published: March 2024

Abstract
Introduction: We aimed to determine the prevalence and landscape of germline mutations among patients with young-onset pancreatic ductal adenocarcinoma (PDAC) as well as their influence in prognosis.

Methods: Patients from two cohorts were studied, the high-risk cohort (HRC), which included 584 PDAC patients who received genetic counseling at The University of Texas MD Anderson Cancer Center, and a general cohort (GC) with 233 metastatic PDAC patients. We defined germline DNA sequencing on 13 known pancreatic cancer susceptibility genes. The prevalence and landscape of mutations were determined, and clinical characteristics including survival were analyzed.

Results: A total of 409 patients underwent genetic testing (277 from HRC and 132 from GC). As expected, the HRC had higher prevalence of germline mutations compared with the GC: 17.3% versus 6.81%. The most common mutations in both cohorts were in BRCA1/2 and mismatch-repair (MMR) genes. Patients younger than 60 years old had significantly higher prevalence of germline mutations in both the HRC [odds ratios (OR), 1.93 ± 1.03–3.70, P = 0.039] and GC (4.78 ± 1.10–32.95, P = 0.036). Furthermore, PDAC patients with germline mutations in the GC had better overall survival than patients without mutations (HR, 0.44; 95% CI of HR, 0.25–0.76, P = 0.030).

Discussion: Germline mutations are highly prevalent in patients with PDAC of early onset and can be predictive of better outcomes. Considering emerging screening strategies for relatives carrying susceptibility genes as well as impact on therapy choices, genetic counseling and testing should be encouraged in PDAC patients, particularly those of young onset. Cancer Prev Res; 11(11); 679–86. ©2018 AACR.
Data from Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762
Authors: Zhang Di , Leal Ana S. , Carapellucci Sarah , Zydeck Kayla , Sporn Michael B. , Liby Karen T.
Published: March 2024

Abstract
Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143–56. ©2017 AACR.
Data from Dietary Advanced Glycation End-products (AGE) and Risk of Breast Cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)
Authors: Omofuma Omonefe O. , Turner David P. , Peterson Lindsay L. , Merchant Anwar T. , Zhang Jiajia , Steck Susan E.
Published: March 2024

Abstract
Advanced glycation end-products (AGEs) are implicated in the pathogenesis of several chronic diseases including cancer. AGEs are produced endogenously but can also be consumed from foods. AGE formation in food is accelerated during cooking at high temperatures. Certain high fat or highly processed foods have high AGE values. The objective of the study was to assign and quantify Nε-carboxymethyl-lysine (CML)-AGE content in food and investigate the association between dietary AGE intake and breast cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The study included women enrolled in the intervention arm who were cancer-free at baseline and completed a baseline questionnaire and food frequency questionnaire (DQX). CML-AGE values were assigned and quantified to foods in the DQX using a published AGE database. Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer among all women, and stratified by race/ethnicity, invasiveness of disease, and hormone receptor status. After a median 11.5 years of follow-up, 1,592 women were diagnosed with breast cancer. Higher CML-AGE intake was associated with increased risk of breast cancer among all women (HRQ5VSQ1, 1.30; 95% CI, 1.04–1.62; Ptrend = 0.04) and in non-Hispanic white women (HRT3VST1, 1.21; 95% CI, 1.02–1.44). Increased CML-AGE intake was associated with increased risk of in situ (HRT3VST1, 1.49; 95% CI, 1.11–2.01) and hormone receptor–positive (HRT3VST1, 1.24; 95% CI, 1.01–1.53) breast cancers. In conclusion, high intake of dietary AGE may contribute to increased breast cancer.
Data from Weight is More Informative than Body Mass Index for Predicting Postmenopausal Breast Cancer Risk: Prospective Family Study Cohort (ProF-SC)
Authors: Ye Zhoufeng , Li Shuai , Dite Gillian S. , Nguyen Tuong L. , MacInnis Robert J. , Andrulis Irene L. , Buys Saundra S. , Daly Mary B. , John Esther M. , Kurian Allison W. , Genkinger Jeanine M. , Chung Wendy K. , Phillips Kelly-Anne , Thorne Heather , Winship Ingrid M. , Milne Roger L. , Dugué Pierre-Antoine , Southey Melissa C. , Giles Graham G. , Terry Mary Beth , Hopper John L.
Published: March 2024

Abstract
We considered whether weight is more informative than body mass index (BMI) = weight/height2 when predicting breast cancer risk for postmenopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women postmenopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort. Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike information criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC = 0.90 and 0.83, respectively; both P = 0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC = 5.32 and 11.64; P = 0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC = 5.47; P = 0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P > 0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with nonadipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk.
Prevention Relevance:
Our results suggest that the relationship between BMI and breast cancer could be due to a relationship between weight and breast cancer, downgraded by inappropriately adjusting for height; potential importance of anthropometric measures other than total body fat; breast cancer risk associations with BMI and weight are across a continuum.
Data from Complementary Longitudinal Serum Biomarkers to CA125 for Early Detection of Ovarian Cancer
Authors: Simmons Archana R. , Fourkala Evangelia Ourania , Gentry-Maharaj Aleksandra , Ryan Andy , Sutton Margie N. , Baggerly Keith , Zheng Hui , Lu Karen H. , Jacobs Ian , Skates Steven , Menon Usha , Bast Robert C.
Published: March 2024

Abstract
Early detection of ovarian cancer has the potential to impact mortality. A multimodal screening strategy where rising CA125 values over time, analyzed with the risk of ovarian cancer algorithm (ROCA), triggers transvaginal sonography and possible surgery has high sensitivity and specificity, but still fails to detect the 20% of early-stage cases that do not express CA125. Use of multiple biomarkers could detect cases missed by CA125. We have studied the sensitivity and lead time of a multi-marker panel (CA125, HE4, MMP-7, and CA 72-4) compared with CA125 alone. We used PRoBE design principles to select preclinical longitudinal specimens from 75 women (50 screen-positive, 25 screen-negative) who developed invasive epithelial ovarian cancer (3–5 serial specimens each) and 547 corresponding healthy controls (1–10 serial specimens each) from the ovarian cancer screening trial, UKCTOCS, in a blinded fashion. We measured the multi-marker concentrations in ultra-low serum volumes (16 μL) utilizing multiplexed bead-based immunoassays with low detection limits, high inter- and intra-assay precision, negligible cross-reactivity, and good correlation with standard immunoassays. While, at least one of the complementary biomarkers rose with CA125 in 44% (22/50) of screen-positive cases, there was no advantage in lead time over CA125. Therefore, we developed single-marker longitudinal algorithms (ROCA-like) to determine the presence of a change point to distinguish between the cases and controls. Using these algorithms, at 98% specificity, HE4 and CA72-4 identified 16% (4/25) of screen-negative cases, while MMP-7 identified none. Taken together, HE4 and CA72-4 show promise as complementary biomarkers to CA125 for longitudinal screening.
Data from Calcium Intake and Risk of Colorectal Cancer According to Tumor-infiltrating T Cells
Authors: Yang Wanshui , Liu Li , Keum NaNa , Qian Zhi Rong , Nowak Jonathan A. , Hamada Tsuyoshi , Song Mingyang , Cao Yin , Nosho Katsuhiko , Smith-Warner Stephanie A. , Zhang Sui , Masugi Yohei , Ng Kimmie , Kosumi Keisuke , Ma Yanan , Garrett Wendy S. , Wang Molin , Nan Hongmei , Giannakis Marios , Meyerhardt Jeffrey A. , Chan Andrew T. , Fuchs Charles S. , Nishihara Reiko , Wu Kana , Giovannucci Edward L. , Ogino Shuji , Zhang Xuehong
Published: March 2024

Abstract
Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell–mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36–0.84; Ptrend = 0.002) for CD8+ T-cell–low but not for CD8+ T-cell–high tumors (HR = 1.02; 95% CI, 0.67–1.55; Ptrend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell–infiltrated tumors were 0.63 (0.42–0.94; Ptrend = 0.01) and 0.89 (0.58–1.35; Ptrend = 0.20) for CD3+; 0.58 (0.39–0.87; Ptrend = 0.006) and 1.04 (0.69–1.58; Ptrend = 0.54) for CD45RO+; and 0.56 (0.36–0.85; Ptrend = 0.006) and 1.10 (0.72–1.67; Ptrend = 0.47) for FOXP3+, although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.
Data from Scutellarin Suppresses Patient-Derived Xenograft Tumor Growth by Directly Targeting AKT in Esophageal Squamous Cell Carcinoma
Authors: Liu Feifei , Zu Xueyin , Xie Xiaomeng , Zhang Yuanyuan , Liu Kangdong , Chen Hanyong , Wang Ting , Bode Ann M. , Dong Zigang , Kim Dong Joon
Published: March 2024

Abstract
Scutellarin is a flavonoid compound that is found in Scutellaria barbata. It has been reported to exhibit anticancer and anti-inflammation activities. However, the anticancer properties of scutellarin and its molecular targets have not been investigated in esophageal squamous cell carcinoma (ESCC). In the current study, we report that scutellarin is a potential AKT inhibitor that suppresses patient-derived xenograft ESCC tumor growth. To identify possible molecular targets of scutellarin, potential candidate proteins were screened by an in vitro kinase assay and Western blotting. We found that scutellarin directly binds to the AKT1/2 proteins and inhibits activities of AKT1/2 in vitro. The AKT protein is activated in ESCC tissues and knockdown of AKT significantly suppresses growth of ESCC cells. Scutellarin significantly inhibits anchorage-dependent and independent cell growth and induces G2 phase cell-cycle arrest in ESCC cells. The inhibition of cell growth by scutellarin is dependent on the expression of the AKT protein. Notably, scutellarin strongly suppresses patient-derived xenograft ESCC tumor growth in an in vivo mouse model. Taken together, our data suggest that scutellarin is a novel AKT inhibitor that may prevent progression of ESCC.
Data from Risk Factors for Recurrence in Patients with Atypical Endometrial Hyperplasia and Endometrioid Adenocarcinoma after Fertility-Sparing Treatments
Authors: Yin Jie , Ma Shuai , Shan Ying , Wang Yongxue , Li Yan , Jin Ying , Pan Lingya
Published: March 2024

Abstract
The aim of this work was to evaluate the risk factors for recurrence in young patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma after fertility-sparing treatments (FST). A retrospective case–control study was designed. Patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma who received FSTs from January 2010 to December 2017 were reviewed. All patients who met the inclusion criteria were divided into a recurrence group and a control group. Risk factors for recurrence- and disease-free survival were evaluated by logistic regression analysis and Cox regression analysis. A total of 127 patients were included, 53 patients in the recurrence group and 74 patients in the control group. No deaths occurred during the follow-up time. The rate of successful pregnancy was 62.5% in the control group and 20.5% in the recurrence group after complete remission (CR) of the primary disease. In a multivariate regression model, after adjusting for other factors, menstruation cycle, progestin type, and regular maintenance treatments after CR were the main risk factors for disease recurrence. Gonadotropin-releasing hormone agonist was mainly used to treat obese patients and was associated with longer progression-free survival (PFS) time compared with that in patients who received high-dose oral progestin such as megestrol acetate [risk ratio (RR), 2.158; 95% confidence interval (CI), 0.948–4.913]. Regular oral progestin also significantly prolonged the PFS time (RR, 4.726; 95% CI, 2.672–8.359). The progestin type used in treatment and regular maintenance treatment of young patients with atypical endometrial hyperplasia and early-stage endometrioid adenocarcinoma after CR might be correlated with disease recurrence.
Data from The COX-2–PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas
Authors: Wei Jie , Zhang Jinyu , Wang Dingzhi , Cen Bo , Lang Jessica D. , DuBois Raymond N.
Published: March 2024

Abstract
The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2–derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4–PI3K–Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4–PI3K–Akt–NFκB–PD-1 signaling pathway. In contrast, inhibiting the COX-2–PGE2–EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion.
Prevention Relevance:
These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs.
Data from Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women
Authors: Zhang Xiaotao , Hoffman Kristi L. , Wei Peng , Elhor Gbito Kplola Y. , Joseph Reji , Li Fangyu , Scheet Paul , Chang Shine , Petrosino Joseph F. , Daniel Carrie R.
Published: March 2024

Abstract
Given the increasing evidence that the oral microbiome is involved in obesity, diabetes, and cancer risk, we investigated baseline oral microbiota profiles in relation to all-cancer incidence among nonsmoking women enrolled in a Texas cohort of first- and second-generation immigrants of Mexican origin. We characterized the 16Sv4 rDNA microbiome in oral mouthwash samples collected at baseline from a representative subset of 305 nonsmoking women, ages 20–75 years. We evaluated within- (alpha) and between-sample (beta) diversity by incident cancer status and applied linear discriminant analysis (LDA) effect size analysis to assess differentially abundant taxa. Diversity and candidate taxa in relation to all-cancer incidence were evaluated in multivariable-adjusted Cox regression models. Over 8.8 median years of follow-up, 31 incident cancer cases were identified and verified. Advanced age, greater acculturation, and cardiometabolic risk factors were associated with all-cancer incidence. Higher alpha diversity (age-adjusted Pdifference < 0.01) and distinct biological communities (Pdifference = 0.002) were observed by incident cancer status. Each unit increase in the Shannon diversity index yielded >8-fold increase in all-cancer and obesity-related cancer risk [multivariable-adjusted HR (95% confidence interval), 8.11 (3.14–20.94) and 10.72 (3.30–34.84), respectively] with similar findings for the inverse Simpson index. Streptococcus was enriched among women who did not develop cancer, while Fusobacterium, Prevotella, Mogibacterium, Campylobacter, Lachnoanaerobaculum, Dialister, and Atopobium were higher among women who developed cancer (LDA score ≥ 3; q-value < 0.01). This initial study of oral microbiota and overall cancer risk in nonsmoking Mexican American women suggests the readily accessible oral microbiota as a promising biomarker.
Prevention Relevance:
Mexican American women suffer a disproportionate burden of chronic health conditions that increase cancer risk. Few investigations of the microbiome, a key determinant of host health, have been conducted among this group. Oral microbiota profiles may provide early and accessible cancer biomarker data on invasive bacteria or community disruptions.
Data from Evidence that EZH2 Deregulation is an Actionable Therapeutic Target for Prevention of Prostate Cancer
Authors: Burkhart Deborah L. , Morel Katherine L. , Wadosky Kristine M. , Labbé David P. , Galbo Phillip M. , Dalimov Zafardjan , Xu Bo , Loda Massimo , Ellis Leigh
Published: March 2024

Abstract
Chemoprevention trials for prostate cancer by androgen receptor or androgen synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical mouse and human models of prostate cancer, we demonstrate that genetic and chemical disruption of EZH2 expression and catalytic activity reversed the HG-PIN phenotype. Furthermore, inhibition of EZH2 function was associated with loss of cellular proliferation and induction of Tp53-dependent senescence. Together, these data provide provocative evidence for EZH2 as an actionable therapeutic target toward prevention of prostate cancer.
Data from Rescue Screens with Secreted Proteins Reveal Compensatory Potential of Receptor Tyrosine Kinases in Driving Cancer Growth
Authors: Harbinski Fred , Craig Vanessa J. , Sanghavi Sneha , Jeffery Douglas , Liu Lijuan , Sheppard Kelly Ann , Wagner Sabrina , Stamm Christelle , Buness Andreas , Chatenay-Rivauday Christian , Yao Yao , He Feng , Lu Chris X. , Guagnano Vito , Metz Thomas , Finan Peter M. , Hofmann Francesco , Sellers William R. , Porter Jeffrey A. , Myer Vic E. , Graus-Porta Diana , Wilson Christopher J. , Buckler Alan , Tiedt Ralph
Published: March 2024

Abstract
The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.

Significance: Although initial tumor responses to kinase inhibitors can be significant, therapeutic benefit is often limited by the emergence of resistance (e.g., as a consequence of mutations in the drug target or through activation of alternative pathways to bypass dependence on the original target). Because the activation of alternative growth-promoting kinases by stimulation with their cognate ligands can constitute such a bypass mechanism, the identification of growth factors as possible mediators of resistance to kinase inhibitors is of clinical interest. Cancer Discov; 2(10); 948–59. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 857.
Data from PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Authors: Ibrahim Yasir H. , García-García Celina , Serra Violeta , He Lei , Torres-Lockhart Kristine , Prat Aleix , Anton Pilar , Cozar Patricia , Guzmán Marta , Grueso Judit , Rodríguez Olga , Calvo Maria Teresa , Aura Claudia , Díez Orland , Rubio Isabel T. , Pérez José , Rodón Jordi , Cortés Javier , Ellisen Leif W. , Scaltriti Maurizio , Baselga José
Published: March 2024

Abstract
PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.

Significance: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs. Cancer Discov; 2(11); 1036–47. ©2012 AACR.

Read the Commentary on this article by Rehman et al., p. 982.

This article is highlighted in the In This Issue feature, p. 961
Data from ATM Mutations in Patients with Hereditary Pancreatic Cancer
Authors: Roberts Nicholas J. , Jiao Yuchen , Yu Jun , Kopelovich Levy , Petersen Gloria M. , Bondy Melissa L. , Gallinger Steven , Schwartz Ann G. , Syngal Sapna , Cote Michele L. , Axilbund Jennifer , Schulick Richard , Ali Syed Z. , Eshleman James R. , Velculescu Victor E. , Goggins Michael , Vogelstein Bert , Papadopoulos Nickolas , Hruban Ralph H. , Kinzler Kenneth W. , Klein Alison P.
Published: March 2024

Abstract
Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition.

Significance: The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes. Cancer Discovery; 2(1): 41–6. ©2011 AACR.

Read the Commentary on this article by Bakker and de Winter, p. 14

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