bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Colonoscopy and Sigmoidoscopy Use among the Average-Risk Population for Colorectal Cancer: A Systematic Review and Trend Analysis
Authors: Cardoso Rafael , Niedermaier Tobias , Chen Chen , Hoffmeister Michael , Brenner Hermann
Published: March 2024

Abstract
Monitoring population-level colonoscopy and sigmoidoscopy use is crucial to estimate the future burden of colorectal cancer and guide screening efforts. We conducted a systematic literature search on colonoscopy and sigmoidoscopy use, published between November 2016 and December 2018 in the databases PubMed and Web of Science to update previous reviews and analyze time trends for various countries. In addition, we used data from the German and European Health Interview Surveys and the National Health Interview Survey to explore recent time trends for Germany and the US, respectively. The literature search yielded 23 new articles: fourteen from the US and nine from Australia, Canada, England, Germany, Saudi Arabia, and South Korea. Colonoscopy use within 10 years was highest and, apart from the youngest age groups eligible for colorectal cancer screening, kept increasing to levels close to 60% in the US and Germany. A recent steep increase was also observed for South Korea. Limited data were available on sigmoidoscopy use; regional studies from the US suggest that sigmoidoscopy has become rarely used. Despite high uptake and ongoing increase in the US, Germany, and South Korea, use of colonoscopy and sigmoidoscopy has either remained low or essentially unknown for the majority of countries.
Data from Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer
Authors: Young Adelaide , Bu Wen , Jiang Weiyu , Ku Amy , Kapali Jyoti , Dhamne Sagar , Qin Lan , Hilsenbeck Susan G. , Du Yi-Chieh Nancy , Li Yi
Published: March 2024

Abstract
Current chemopreventive strategies require 3–5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention.
Prevention Relevance:
This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.
Data from Dietary Methyl Donor Depletion Suppresses Intestinal Adenoma Development
Authors: Hanley Matthew P. , Kadaveru Krishna , Perret Christine , Giardina Charles , Rosenberg Daniel W.
Published: March 2024

Abstract
The role of folate one-carbon metabolism in colorectal cancer development is controversial, with nutritional intervention studies producing conflicting results. It has been reported that ApcMin/+ mice maintained on a diet deficient in the methyl donors folic acid, methionine, choline, and vitamin B12, and supplemented with homocysteine, show a greater than 95% reduction in intestinal tumor development. The present study extends these findings and shows that tumor protection afforded by dietary methyl donor deficiency (MDD) is long-lasting. After 11 weeks of MDD, tumor protection persisted for at least an additional 7 weeks of methyl donor repletion (22.2 ± 3.5 vs. 70.2 ± 4.6 tumors per mouse; P < 0.01). Sustained tumor protection was associated with a reduction in intestinal crypt length (26%, P < 0.01), crypt cell division and crypt fission, and an increase in apoptosis of both normal crypts and tumors (4.9- and 3.2-fold, respectively, P < 0.01). MDD also caused a significant reduction in the number of Dclk1-positive cells in the intestine (62%, P < 0.01), a long-lived crypt cell with cancer stem cell potential. Several undesirable effects associated with methyl donor restriction (e.g., reduced body weight gain) were shown to be transient and readily reversible following methyl donor repletion. Taken together, these results indicate that even temporary dietary methyl donor restriction in adenoma-prone mice can induce persistent changes to the intestinal epithelium and provide long-lasting tumor protection. These data also suggest that transient reductions in dietary methyl donor consumption should be considered when studying the impact of folate on colon cancer risk in humans. Cancer Prev Res; 9(10); 812–20. ©2016 AACR.
Data from Metabolomics Profiles of Hepatocellular Carcinoma in a Korean Prospective Cohort: The Korean Cancer Prevention Study-II
Authors: Jee Sun Ha , Kim Minjoo , Kim Minkyung , Yoo Hye Jin , Kim Hyungyoon , Jung Keum Ji , Hong Seri , Lee Jong Ho
Published: March 2024

Abstract
In the prospective Korean Cancer Prevention Study-II (KCPS-II), we investigated the application of metabolomics to differentiate subjects with incident hepatocellular carcinoma (HCC group) from subjects who remained free of cancer (control group) during a mean follow-up period of 7 years with the aim of identifying valuable metabolic biomarkers for HCC. We used baseline serum samples from 75 subjects with incident HCC and 134 age- and gender-matched cancer-free subjects. Serum metabolic profiles associated with HCC incidence were investigated via metabolomics analysis. Compared with the control group, the HCC group showed significantly higher serum levels of aspartate aminotransferase (AST), alanine aminotransferase, and γ-glutamyl transpeptidase. At baseline, compared with the control group, the HCC group showed significantly higher levels of 9 metabolites, including leucine, 5-hydroxyhexanoic acid, phenylalanine, tyrosine, arachidonic acid, and tauroursodeoxycholic acid (TUDCA), but lower levels of 28 metabolites, including oleamide, androsterone sulfate, L-palmitoylcarnitine, lysophosphatidic acid (LPA) 16:0, LPA 18:1, and lysophosphatidylcholines (lysoPC). Multiple linear regression revealed that the incidence of HCC was associated with the levels of tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA (adjusted R2 = 0.514, P = 0.036). This study showed the clinical relevance of the dysregulation of not only branched amino acids, aromatic amino acids, and lysoPCs but also bile acid biosynthesis and linoleic acid, arachidonic acid, and fatty acid metabolism. In addition, tyrosine, AST, lysoPCs (16:1, 20:3), oleamide, 5-hydroxyhexanoic acid, androsterone sulfate, and TUDCA were identified as independent variables associated with the incidence of HCC. Cancer Prev Res; 11(5); 303–12. ©2018 AACR.
Data from Association Between Diet and Fusobacterium nucleatum in the Feces of Healthy Adults: A Hospital-based Cross-sectional Study
Authors: Narii Nobuhiro , Zha Ling , Sobue Tomotaka , Kitamura Tetsuhisa , Shiba Satoshi , Mizutani Sayaka , Yamada Takuji , Yachida Shinichi
Published: March 2024

Abstract
Fusobacterium nucleatum is involved in the development and progression of colorectal cancer. Although the gut microbiota is influenced by diet, studies on the association between diet and F. nucleatum are limited. We aimed to evaluate the association between various dietary factors and fecal F. nucleatum in healthy adults without a history of colorectal cancer or precancerous lesions. This was a cross-sectional study. Subjects who underwent total colonoscopy at the National Cancer Center Hospital (Tokyo, Japan) were included. Healthy subjects (n = 212) were divided into two groups according to the presence or absence of F. nucleatum in their feces which was calculated from data of whole-genome shotgun sequencing, with the group with F. nucleatum serving as cases and the group without F. nucleatum serving as controls. Multivariable logistic regression analysis adjusted potential confounders was conducted to estimate the associations between dietary intake and nutrients estimated by a validated food frequency questionnaire and the presence of F. nucleatum in the feces. There was a significant inverse association between dairy products and the presence of fecal F. nucleatum [high vs. low; OR, 0.41; 95% confidence interval, 0.17–0.95; Ptrend, 0.039]. These results may have important implications for colorectal cancer prevention through nutritional intervention.
Prevention Relevance:
F. nucleatum is well known as a colorectal cancer–associated bacterium. Dietary habits alter the composition and function of the intestinal microbiota. A high intake of dairy products in healthy adults may reduce F. nucleatum and prevent colorectal cancer.
Data from Short-term PI3K Inhibition Prevents Breast Cancer in Preclinical Models
Authors: Ku Amy T. , Young Adelaide I.J. , Ibrahim Ahmed Atef , Bu Wen , Jiang Weiyu , Lin Meng , Williams Laterrica C. , McCue Bryant Lee , Miles George , Nagi Chandandeep , Behbod Fariba , Li Yi
Published: March 2024

Abstract
Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.
Prevention Relevance:
PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.
Data from Estrogen-DNA Adducts and Breast Cancer Risk in Premenopausal Asian Women
Authors: Lin Ching-Hung , Zahid Muhammad , Kuo Wen-Hung , Hu Fu-Chang , Wang Ming-Yang , Chen I-Chun , Beseler Cheryl L. , Mondal Bodhisattwa , Lu Yen-Shen , Rogan Eleanor G. , Cheng Ann-Lii
Published: March 2024

Abstract
The incidence of breast cancer among premenopausal women has been increasing rapidly in recent decades in East Asia. This case–control study investigated whether estrogen-DNA adducts were associated with breast cancer risk in Taiwan. The control group (n = 146) comprised healthy female volunteers and women with non-proliferative breast disease. The case group (n = 221) comprised women either with proliferative benign breast disease or breast cancer. The ratios of estrogen-DNA adducts to their respective metabolites and conjugates in plasma were analyzed using ultraperformance LC/MS-MS. The SNPs of CYP1A1, CYP1B1, and COMT were genotyped. Logistic regression model was used to compare the estrogen-DNA adduct ratios between the two groups. The estrogen-DNA adduct ratio in the case group was significantly higher than that in the control group (median ratio: 58.52 vs. 29.36, P = 0.004). A multiple logistic regression model demonstrated that a unit increase in the natural log of the estrogen-DNA adduct ratio in premenopausal women was a significant predictor of breast cancer risk, with an estimated hazard ratio of 1.718 (1.444−2.046, P < 0.001). However, the CYP1A1, CYP1B1, and COMT SNPs were not associated with the estrogen-DNA adduct ratios. In conclusion, plasma estrogen-DNA adduct ratio was associated with the presence of breast cancer or proliferating benign breast disease in premenopausal women in Taiwan.
Prevention Relevance:
This study provides evidence that endogenous estrogen-induced genotoxicity may contribute to the carcinogenesis of breast cancer in premenopausal Asian women. This work could have important preventive implication for the emerging disease in East Asia.
Data from The mTORC1 Inhibitor Everolimus Prevents and Treats Eμ-Myc Lymphoma by Restoring Oncogene-Induced Senescence
Authors: Wall Meaghan , Poortinga Gretchen , Stanley Kym L. , Lindemann Ralph K. , Bots Michael , Chan Christopher J. , Bywater Megan J. , Kinross Kathryn M. , Astle Megan V. , Waldeck Kelly , Hannan Katherine M. , Shortt Jake , Smyth Mark J. , Lowe Scott W. , Hannan Ross D. , Pearson Richard B. , Johnstone Ricky W. , McArthur Grant A.
Published: March 2024

Abstract
MYC deregulation is common in human cancer. IG-MYC translocations that are modeled in Eμ-Myc mice occur in almost all cases of Burkitt lymphoma as well as in other B-cell lymphoproliferative disorders. Deregulated expression of MYC results in increased mTOR complex 1 (mTORC1) signaling. As tumors with mTORC1 activation are sensitive to mTORC1 inhibition, we used everolimus, a potent and specific mTORC1 inhibitor, to test the requirement for mTORC1 in the initiation and maintenance of Eμ-Myc lymphoma. Everolimus selectively cleared premalignant B cells from the bone marrow and spleen, restored a normal pattern of B-cell differentiation, and strongly protected against lymphoma development. Established Eμ-Myc lymphoma also regressed after everolimus therapy. Therapeutic response correlated with a cellular senescence phenotype and induction of p53 activity. Therefore, mTORC1-dependent evasion of senescence is critical for cellular transformation and tumor maintenance by MYC in B lymphocytes.

Significance: This work provides novel insights into the requirements for MYC-induced oncogenesis by showing that mTORC1 activity is necessary to bypass senescence during transformation of B lymphocytes. Furthermore, tumor eradication through senescence elicited by targeted inhibition of mTORC1 identifies a previously uncharacterized mechanism responsible for significant anticancer activity of rapamycin analogues and serves as proof-of-concept that senescence can be harnessed for therapeutic benefit. Cancer Discov; 3(1); 82–95. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from A Hormone–DNA Repair Circuit Governs the Response to Genotoxic Insult
Authors: Goodwin Jonathan F. , Schiewer Matthew J. , Dean Jeffry L. , Schrecengost Randy S. , de Leeuw Renée , Han Sumin , Ma Teng , Den Robert B. , Dicker Adam P. , Feng Felix Y. , Knudsen Karen E.
Published: March 2024

Abstract
Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings show that androgen receptor (AR) activity is induced by DNA damage and promotes expression and activation of a gene expression program governing DNA repair. Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo. Mechanistically, DNA-dependent protein kinase catalytic subunit (DNAPKcs) was identified as a key target of AR after damage, controlling AR-mediated DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these studies identify the AR–DNAPKcs circuit as a major effector of DNA repair and therapeutic resistance and establish a new node for therapeutic intervention in advanced disease.

Significance: The present study identifies for the first time a positive feedback circuit linking hormone action to the DNA damage response and shows the significant impact of this process on tumor progression and therapeutic response. These provocative findings provide the foundation for development of novel nodes of therapeutic intervention for advanced disease. Cancer Discov; 3(11); 1254–71. ©2013 AACR.

See related commentary by Bartek et al., p. 1222

This article is highlighted in the In This Issue feature, p. 1207
Data from Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia
Authors: Pemovska Tea , Kontro Mika , Yadav Bhagwan , Edgren Henrik , Eldfors Samuli , Szwajda Agnieszka , Almusa Henrikki , Bespalov Maxim M. , Ellonen Pekka , Elonen Erkki , Gjertsen Bjørn T. , Karjalainen Riikka , Kulesskiy Evgeny , Lagström Sonja , Lehto Anna , Lepistö Maija , Lundán Tuija , Majumder Muntasir Mamun , Marti Jesus M. Lopez , Mattila Pirkko , Murumägi Astrid , Mustjoki Satu , Palva Aino , Parsons Alun , Pirttinen Tero , Rämet Maria E. , Suvela Minna , Turunen Laura , Västrik Imre , Wolf Maija , Knowles Jonathan , Aittokallio Tero , Heckman Caroline A. , Porkka Kimmo , Kallioniemi Olli , Wennerberg Krister
Published: March 2024

Abstract
We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profiling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered five major taxonomic drug-response subtypes based on DSRT profiles, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3-ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed significant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs.

Significance: Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing. Cancer Discov; 3(12); 1416–29. ©2013 AACR.

See related commentary by Hourigan and Karp, p. 1336

This article is highlighted in the In This Issue feature, p. 1317
Data from Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma
Authors: Girotti Maria R. , Pedersen Malin , Sanchez-Laorden Berta , Viros Amaya , Turajlic Samra , Niculescu-Duvaz Dan , Zambon Alfonso , Sinclair John , Hayes Andrew , Gore Martin , Lorigan Paul , Springer Caroline , Larkin James , Jorgensen Claus , Marais Richard
Published: March 2024

Abstract
We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)–SRC family kinase (SFK)–STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of the resistant tumors in immunocompromised mice. Our data show that BRAF inhibitor-mediated activation of EGFR–SFK–STAT3 signaling can mediate resistance in patients with BRAF-mutant melanoma. We describe 2 treatments that seem to overcome this resistance and could deliver therapeutic efficacy in patients with drug-resistant BRAF-mutant melanoma.

Significance: Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratified for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF-mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients. Cancer Discov; 3(2); 158–67. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 125
Data from A Genome-Scale RNA Interference Screen Implicates NF1 Loss in Resistance to RAF Inhibition
Authors: Whittaker Steven R. , Theurillat Jean-Philippe , Van Allen Eliezer , Wagle Nikhil , Hsiao Jessica , Cowley Glenn S. , Schadendorf Dirk , Root David E. , Garraway Levi A.
Published: March 2024

Abstract
RAF inhibitors such as vemurafenib and dabrafenib block BRAF–mediated cell proliferation and achieve meaningful clinical benefit in the vast majority of patients with BRAFV600E-mutant melanoma. However, some patients do not respond to this regimen, and nearly all progress to therapeutic resistance. We used a pooled RNA interference screen targeting more than 16,500 genes to discover loss-of-function events that could drive resistance to RAF inhibition. The highest ranking gene was NF1, which encodes neurofibromin, a tumor suppressor that inhibits RAS activity. NF1 loss mediates resistance to RAF and mitogen-activated protein kinase (MAPK) kinase kinase (MEK) inhibitors through sustained MAPK pathway activation. However, cells lacking NF1 retained sensitivity to the irreversible RAF inhibitor AZ628 and an ERK inhibitor. NF1 mutations were observed in BRAF–mutant tumor cells that are intrinsically resistant to RAF inhibition and in melanoma tumors obtained from patients exhibiting resistance to vemurafenib, thus showing the clinical potential for NF1-driven resistance to RAF/MEK-targeted therapies.

Significance: This work identifies functional loss of NF1 as a mediator of resistance to RAF inhibitors in BRAFV600E-mutant cancers. Furthermore, we nominate new therapeutic modalities to treat this mechanism of resistance. Cancer Discov; 3(3); 350–62. ©2012 AACR.

See related commentary by Gibney and Smalley, p. 260

This article is highlighted in the In This Issue feature, p. 239
Data from Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer
Authors: Bose Ron , Kavuri Shyam M. , Searleman Adam C. , Shen Wei , Shen Dong , Koboldt Daniel C. , Monsey John , Goel Nicholas , Aronson Adam B. , Li Shunqiang , Ma Cynthia X. , Ding Li , Mardis Elaine R. , Ellis Matthew J.
Published: March 2024

Abstract
Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755–759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.

Significance: We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs. Cancer Discov; 3(2); 224–37. ©2013 AACR.

See related commentary by Weigelt and Reis-Filho, p. 145

This article is highlighted in the In This Issue feature, p. 125
Data from Chimeric Transcript Generated by cis-Splicing of Adjacent Genes Regulates Prostate Cancer Cell Proliferation
Authors: Zhang Yanmei , Gong Mei , Yuan Huiling , Park Hong G. , Frierson Henry F. , Li Hui
Published: March 2024

Abstract
Gene fusion is a common event in cancer. The fusion RNA and protein products often play causal roles in tumorigenesis and therefore represent ideal diagnostic and therapeutic targets. Formerly, fusion chimeric products in cancer were thought to be produced solely by chromosomal translocation. Here, we show that a chimeric SLC45A3-ELK4 RNA is generated in the absence of chromosomal rearrangement. We showed that it is not a product of RNA trans-splicing, but formed by cis-splicing of adjacent genes/read-through. The binding of CCCTC-binding factor (CTCF) to the insulator sequences inversely correlates with the expression of the chimera transcript. The SLC45A3-ELK4 fusion, but not wild-type, ELK4 plays important roles in regulating cell growth in both androgen-dependent and -independent prostate cancer cells. The level of the chimeric transcript correlates with disease progression, with the highest levels in prostate cancer metastases. Our results suggest that gene fusions can arise from cis-splicing of adjacent genes without corresponding DNA changes.

Significance: With the absence of corresponding DNA rearrangement, chimeric fusion SLC45A3-ELK4 transcript in prostate cancer cells is generated by cis-splicing of adjacent genes/gene read-through instead of trans-splicing. SLC45A3-ELK4 controls prostate cancer cell proliferation, and the chimera level correlates with prostate cancer disease progression. Cancer Discov; 2(7); 598–607. ©2012 AACR.

Read the Commentary on this article by Kumar-Sinha et al., p. 582.

This article is highlighted in the In This Issue feature, p. 569.
Data from Bone Marrow–Derived Gr1+ Cells Can Generate a Metastasis-Resistant Microenvironment Via Induced Secretion of Thrombospondin-1
Authors: Catena Raúl , Bhattacharya Nandita , El Rayes Tina , Wang Suming , Choi Hyejin , Gao Dingcheng , Ryu Seongho , Joshi Natasha , Bielenberg Diane , Lee Sharrell B. , Haukaas Svein A. , Gravdal Karsten , Halvorsen Ole J. , Akslen Lars A. , Watnick Randolph S. , Mittal Vivek
Published: March 2024

Abstract
Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow–derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations, the otherwise prometastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. Bone marrow–specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by bone marrow transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacologic inducer of Tsp-1 in Gr1+ bone marrow cells, which dramatically suppressed metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer.

Significance: The mechanisms of metastasis suppression are poorly understood. Here, we have identified a novel mechanism whereby metastasis-incompetent tumors generate metastasis-suppressive microenvironments in distant organs by inducing Tsp-1 expression in the bone marrow–derived Gr1+ myeloid cells. A 5-amino acid peptide with Tsp-1–inducing activity was identified as a therapeutic agent against metastatic cancer. Cancer Discov; 3(5); 578–89. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 471
Data from SF3B1 Mutations Are Associated with Alternative Splicing in Uveal Melanoma
Authors: Furney Simon J. , Pedersen Malin , Gentien David , Dumont Amaury G. , Rapinat Audrey , Desjardins Laurence , Turajlic Samra , Piperno-Neumann Sophie , de la Grange Pierre , Roman-Roman Sergio , Stern Marc-Henri , Marais Richard
Published: March 2024

Abstract
Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas. We observed only approximately 2,000 predicted somatic single-nucleotide variants per tumor and low levels of aneuploidy. We did not observe an ultraviolet radiation DNA damage signature, but identified SF3B1 mutations in three samples and a further 15 mutations in an extension cohort of 105 samples. SF3B1 mutations were associated with good prognosis and were rarely coincident with BAP1 mutations. SF3B1 encodes a component of the spliceosome, and RNA sequencing revealed that SF3B1 mutations were associated with differential alternative splicing of protein coding genes, including ABCC5 and UQCC, and of the long noncoding RNA CRNDE.

Significance: Our data show that despite its dismal prognosis, uveal melanoma is a relatively simple genetic disease characterized by recurrent chromosomal losses and gains and a low mutational burden. We show that SF3B1 is recurrently mutated in uveal melanoma, and the mutations are associated with aberrant alternative splicing. Cancer Discov; 3(10); 1122–9. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1083
Data from Senescence Sensitivity of Breast Cancer Cells Is Defined by Positive Feedback Loop between CIP2A and E2F1
Authors: Laine Anni , Sihto Harri , Come Christophe , Rosenfeldt Mathias T. , Zwolinska Aleksandra , Niemelä Minna , Khanna Anchit , Chan Edward K. , Kähäri Veli-Matti , Kellokumpu-Lehtinen Pirkko-Liisa , Sansom Owen J. , Evan Gerard I. , Junttila Melissa R. , Ryan Kevin M. , Marine Jean-Christophe , Joensuu Heikki , Westermarck Jukka
Published: March 2024

Abstract
Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53–p21 pathway.

Significance: It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratification strategies for selection of patients to receive senescence-inducing cancer therapies. Cancer Discov; 3(2); 182–97. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 125
Data from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
Authors: Sanda Takaomi , Tyner Jeffrey W. , Gutierrez Alejandro , Ngo Vu N. , Glover Jason , Chang Bill H. , Yost Arla , Ma Wenxue , Fleischman Angela G. , Zhou Wenjun , Yang Yandan , Kleppe Maria , Ahn Yebin , Tatarek Jessica , Kelliher Michelle A. , Neuberg Donna S. , Levine Ross L. , Moriggl Richard , Müller Mathias , Gray Nathanael S. , Jamieson Catriona H.M. , Weng Andrew P. , Staudt Louis M. , Druker Brian J. , Look A. Thomas
Published: March 2024

Abstract
Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the Janus-activated kinase (JAK) tyrosine kinase family, TYK2, and its downstream effector STAT1, in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently showed TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK activity induced T-ALL cell death. Activation of this TYK2–STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of interleukin (IL)-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the antiapoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2–STAT1–BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway.

Significance: In recent years, “pathway dependence” has been revealed in specific types of human cancer, which can be important because they pinpoint proteins that are particularly vulnerable to antitumor-targeted inhibition (so-called Achilles' heel proteins). Here, we use RNAi technology to identify a novel oncogenic pathway that involves aberrant activation of the TYK2 tyrosine kinase and its downstream substrate, STAT1, which ultimately promotes T-ALL cell survival through the upregulation of BCL2 expression. Cancer Discov; 3(5); 564–77. ©2013 AACR.

See related commentary by Fontan and Melnick, p. 494

This article is highlighted in the In This Issue feature, p. 471
Data from Increased Levels of COX-2 and Prostaglandin E2 Contribute to Elevated Aromatase Expression in Inflamed Breast Tissue of Obese Women
Authors: Subbaramaiah Kotha , Morris Patrick G. , Zhou Xi Kathy , Morrow Monica , Du Baoheng , Giri Dilip , Kopelovich Levy , Hudis Clifford A. , Dannenberg Andrew J.
Published: March 2024

Abstract
Obesity is a risk factor for hormone receptor-positive breast cancer in postmenopausal women. Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. We previously showed that aromatase expression and activity are increased in the breast tissue of overweight and obese women in the presence of characteristic inflammatory foci [crown-like structures of the breast (CLS-B)]. In preclinical studies, proinflammatory prostaglandin E2 (PGE2) is a determinant of aromatase expression. We provide evidence that cyclooxygenase (COX)-2–derived PGE2 stimulates the cyclic AMP (cAMP)→PKA signal transduction pathway that activates CYP19 transcription, resulting in increased aromatase expression and elevated progesterone receptor levels in breast tissues from overweight and obese women. We further demonstrate that a measure of in-breast inflammation (CLS-B index) is a better correlate of these biologic end points than body mass index. The obesity→inflammation→aromatase axis is likely to contribute to the increased risk of hormone receptor-positive breast cancer and the worse prognosis of obese patients with breast cancer.

Significance: We show that obesity-associated inflammatory foci in the human breast are associated with elevated COX-2 levels and activation of the PGE2→cAMP→PKA signal transduction pathway resulting in increased aromatase expression. These findings help to explain the link among obesity, low-grade chronic inflammation, and breast cancer with important clinical implications. Cancer Discov; 2(4); 356–65. ©2012 AACR.

Read the Commentary on this article by Wang and DuBois, p. 308

This article is highlighted in the In This Issue feature, p. 288
Data from Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer
Authors: Hammerman Peter S. , Sos Martin L. , Ramos Alex H. , Xu Chunxiao , Dutt Amit , Zhou Wenjun , Brace Lear E. , Woods Brittany A. , Lin Wenchu , Zhang Jianming , Deng Xianming , Lim Sang Min , Heynck Stefanie , Peifer Martin , Simard Jeffrey R. , Lawrence Michael S. , Onofrio Robert C. , Salvesen Helga B. , Seidel Danila , Zander Thomas , Heuckmann Johannes M. , Soltermann Alex , Moch Holger , Koker Mirjam , Leenders Frauke , Gabler Franziska , Querings Silvia , Ansén Sascha , Brambilla Elisabeth , Brambilla Christian , Lorimier Philippe , Brustugun Odd Terje , Helland Åslaug , Petersen Iver , Clement Joachim H. , Groen Harry , Timens Wim , Sietsma Hannie , Stoelben Erich , Wolf Jürgen , Beer David G. , Tsao Ming Sound , Hanna Megan , Hatton Charles , Eck Michael J. , Janne Pasi A. , Johnson Bruce E. , Winckler Wendy , Greulich Heidi , Bass Adam J. , Cho Jeonghee , Rauh Daniel , Gray Nathanael S. , Wong Kwok-Kin , Haura Eric B. , Thomas Roman K. , Meyerson Matthew
Published: March 2024

Abstract
Although genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations that drive squamous cell cancer (SCC) of the lung. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of lung SCCs and cell lines. Lung SCC cell lines harboring DDR2 mutations were selectively killed by knockdown of DDR2 by RNA interference or by treatment with the multitargeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation that was blocked by dasatinib. A patient with lung SCC that responded to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. Because dasatinib is already approved for use, these findings could be used to rapidly generate clinical trials.

Significance: DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib. These findings provide a rationale for designing clinical trials with the FDA-approved drug dasatinib in patients with lung SCCs. Cancer Discovery; 1(1); 78–89. ©2011 AACR.

Read the Commentary on this article by Ohashi and Pao, p. 23

This article is highlighted in the In This Issue feature, p. 4
Data from Targeting the Wnt Pathway in Synovial Sarcoma Models
Authors: Barham Whitney , Frump Andrea L. , Sherrill Taylor P. , Garcia Christina B. , Saito-Diaz Kenyi , VanSaun Michael N. , Fingleton Barbara , Gleaves Linda , Orton Darren , Capecchi Mario R. , Blackwell Timothy S. , Lee Ethan , Yull Fiona , Eid Josiane E.
Published: March 2024

Abstract
Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT–SSX (SS18–SSX), drives sarcoma initiation and development. The exact mechanism of SYT–SSX oncogenic function remains unknown. In an SYT–SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT–SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT–SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents.

Significance: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT–SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans. Cancer Discov; 3(11); 1286–1301. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1207
Data from Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling
Authors: Young Amy , Lou David , McCormick Frank
Published: March 2024

Abstract
H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and nonredundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, whereas wild-type Ras mediates signaling downstream of activated receptor tyrosine kinases (RTK). We show that both are necessary for exponential growth of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA oligonucleotides relieves this negative feedback, leading to the hyperactivation of EGFR and wild-type Ras signaling. Consistent with this model, combining oncogenic Ras depletion with EGFR inhibition potently increases cell death.

Significance: The results of this study highlight a novel role for wild-type Ras signaling in cancer cells harboring oncogenic RAS mutations. Furthermore, these findings reveal that therapeutically targeting oncogenic Ras signaling alone may be ineffective owing to feedback activation of RTKs, and suggest that blocking upstream RTKs in combination with downstream effector pathways may be beneficial in the treatment of Ras-mutant tumors. Cancer Discov; 3(1); 112–23. ©2012 AACR.

See related commentary by Hayes and Der, p. 24

This article is highlighted in the In This Issue feature, p. 1
Data from Genomic Complexity and AKT Dependence in Serous Ovarian Cancer
Authors: Hanrahan Aphrothiti J. , Schultz Nikolaus , Westfal Maggie L. , Sakr Rita A. , Giri Dilip D. , Scarperi Stefano , Janikariman Manickam , Olvera Narciso , Stevens Ellen V. , She Qing-Bai , Aghajanian Carol , King Tari A. , de Stanchina Elisa , Spriggs David R. , Heguy Adriana , Taylor Barry S. , Sander Chris , Rosen Neal , Levine Douglas A. , Solit David B.
Published: March 2024

Abstract
Effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer. To explore the role of phosphatidylinositol 3-kinase (PI3K)/AKT signaling in this disease, we performed a genetic and functional analysis of ovarian cancer cell lines and tumors. PI3K pathway alterations were common in both, but the spectrum of mutational changes differed. Genetic activation of the pathway was necessary, but not sufficient, to confer sensitivity to selective inhibition of AKT and cells with RAS pathway alterations or RB1 loss were resistant to AKT inhibition, whether or not they had coexistent PI3K/AKT pathway activation. Inhibition of AKT1 caused growth arrest in a subset of ovarian cell lines, but not in those with AKT3 expression, which required pan-AKT inhibition. Thus, a subset of ovarian tumors is sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient's tumor.

Significance: A subset of ovarian cancers exhibits AKT pathway activation and is sensitive to selective AKT inhibition. Ovarian tumors exhibit significant genetic heterogeneity and thus an individualized approach based on real-time, detailed genomic and proteomic characterization of individual tumors will be required for the successful application of PI3K/AKT pathway inhibitors in this disease. Cancer Discovery; 2(1); 56–67. ©2011 AACR.

Read the Commentary on this article by Bast and Mills, p. 16

This article is highlighted in the In This Issue feature, p. 1
Data from Hypoxia-Dependent Modification of Collagen Networks Promotes Sarcoma Metastasis
Authors: Eisinger-Mathason T.S. Karin , Zhang Minsi , Qiu Qiong , Skuli Nicolas , Nakazawa Michael S. , Karakasheva Tatiana , Mucaj Vera , Shay Jessica E.S. , Stangenberg Lars , Sadri Navid , Puré Ellen , Yoon Sam S. , Kirsch David G. , Simon M. Celeste
Published: March 2024

Abstract
Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α–deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination.

Significance: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifically the collagen-modifying enzyme PLOD2. Cancer Discov; 3(10); 1190–1205. ©2013 AACR.

See related commentary by Vanharanta and Massagué, p. 1103

This article is highlighted in the In This Issue feature, p. 1083