bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Nrf2 Prevents Initiation but Accelerates Progression through the Kras Signaling Pathway during Lung Carcinogenesis
Authors: Satoh Hironori , Moriguchi Takashi , Takai Jun , Ebina Masahito , Yamamoto Masayuki
Published: March 2024

Abstract
Nrf2 (Nfe2l2) governs cellular defenses against oxidative and electrophilic stresses and protects against chemical carcinogenesis. However, many cancers have been found to accumulate NRF2 protein, raising questions of precisely how Nrf2 contributes to carcinogenesis. In this report, we explored such questions in an established urethane-induced multistep model of lung carcinogenesis. Consistent with earlier observations, Nrf2-deficient (Nrf2−/−) mice exhibited a relative increase in tumor foci by 8 weeks after urethane administration. However, after 16 weeks, we observed a relative reduction in the number of tumors with more malignant characteristics in Nrf2−/− mice. Furthermore, all Nrf2+/+ tumors harbored activated mutations in Kras, whereas Nrf2−/− tumors were rarely associated with similar Kras mutations. Overall, our results established that Nrf2 has two roles during carcinogenesis, one of which is preventive during tumor initiation and the second that promotes malignant progression. These findings establish Nrf2 inhibitors as rational tools to prevent malignant progression in lung cancer, whereas Nrf2 activators are more suited for lung cancer prevention. Cancer Res; 73(13); 4158–68. ©2013 AACR.
Data from MiR-155 Is a Liposarcoma Oncogene That Targets Casein Kinase-1α and Enhances β-Catenin Signaling
Authors: Zhang Pingyu , Bill Katelynn , Liu Juehui , Young Eric , Peng Tingsheng , Bolshakov Svetlana , Hoffman Aviad , Song Yechun , Demicco Elizabeth G. , Terrada Dolores Lopez , Creighton Chad J. , Anderson Matthew L. , Lazar Alexander J. , Calin George G. , Pollock Raphael E. , Lev Dina
Published: March 2024

Abstract
Liposarcoma can be an aggressive, debilitating, and fatal malignancy. In this study, we identifed miRNAs associated with the differentiation status of liposarcoma to gain insight into the basis for its progression. miRNA expression profiles determined in human tumors and normal fat specimens identified a dedifferentiated tumor expression signature consisting of 35 miRNAs. Deregulated miRNA expression was confirmed in a second independent sample cohort. The miR-155 was the most overexpressed miRNA and functional investigations assigned an important role in the growth of dedifferentiated liposarcoma cell lines. Transient or stable knockdown of miR-155 retarded tumor cell growth, decreased colony formation, and induced G1-S cell-cycle arrest in vitro and blocked tumor growth in murine xenografts in vivo. We identified casein kinase 1α (CK1α) as a direct target of miR-155 control which enhanced β-catenin signaling and cyclin D1 expression, promoting tumor cell growth. In summary, our results point to important functions for miR-155 and β-catenin signaling in progression of liposarcoma, revealing mechanistic vulnerabilities that might be exploited for both prognostic and therapeutic purposes. Cancer Res; 72(7); 1751–62. ©2012 AACR.
Data from BMK1 Kinase Suppresses Epithelial–Mesenchymal Transition through the Akt/GSK3β Signaling Pathway
Authors: Chen Runqiang , Yang Qingkai , Lee Jiing-Dwan
Published: March 2024

Abstract
Epithelial–mesenchymal transition (EMT) plays a crucial role in the development of cancer metastasis. The mitogen-activated protein (MAP) kinases extracellular signal–regulated kinase, c-jun-NH2-kinase, and p38 have been implicated in promoting EMT, but a role for the MAP kinase BMK1 has not been studied. Here, we report that BMK1 signaling suppresses EMT. BMK1 elevation augmented E-cadherin–mediated cell–cell adhesion, downregulated mesenchymal markers, and decreased cell motility. Conversely, BMK1 silencing attenuated E-cadherin–mediated cell–cell adhesion, upregulated mesenchymal markers, and stimulated cell motility. BMK1 depletion dramatically increased the accumulation of endogenous Snail in the nuclear compartment. Snail accumulation was mediated by Akt/GSK3β signaling, which was activated by a modulation in the expression of the mTOR inhibitor DEPTOR. In support of these observations, BMK1 depletion promoted metastasis in vivo. Together, our findings reveal a novel mechanism of EMT control via mTOR/Akt inhibition that suppresses cancer metastasis. Cancer Res; 72(6); 1579–87. ©2012 AACR.
Data from Oncogenic NRAS, Required for Pathogenesis of Embryonic Rhabdomyosarcoma, Relies upon the HMGA2–IGF2BP2 Pathway
Authors: Li Zhizhong , Zhang Yunyu , Ramanujan Krishnan , Ma Yan , Kirsch David G. , Glass David J.
Published: March 2024

Abstract
Embryonic rhabdomyosarcoma (ERMS) is the most common soft-tissue tumor in children. Here, we report the identification of the minor groove DNA-binding factor high mobility group AT-hook 2 (HMGA2) as a driver of ERMS development. HMGA2 was highly expressed in normal myoblasts and ERMS cells, where its expression was essential to maintain cell proliferation, survival in vitro, and tumor outgrowth in vivo. Mechanistic investigations revealed that upregulation of the insulin–like growth factor (IGF) mRNA-binding protein IGF2BP2 was critical for HMGA2 action. In particular, IGF2BP2 was essential for mRNA and protein stability of NRAS, a frequently mutated gene in ERMS. shRNA-mediated attenuation of NRAS or pharmacologic inhibition of the MAP–ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) effector pathway showed that NRAS and NRAS-mediated signaling was required for tumor maintenance. Taken together, these findings implicate the HMGA2–IGFBP2–NRAS signaling pathway as a critical oncogenic driver in ERMS. Cancer Res; 73(10); 3041–50. ©2013 AACR.
Data from Dachshund Binds p53 to Block the Growth of Lung Adenocarcinoma Cells
Authors: Chen Ke , Wu Kongming , Cai Shaoxin , Zhang Wei , Zhou Jie , Wang Jing , Ertel Adam , Li Zhiping , Rui Hallgeir , Quong Andrew , Lisanti Michael P. , Tozeren Aydin , Tanes Ceylan , Addya Sankar , Gormley Michael , Wang Chenguang , McMahon Steven B. , Pestell Richard G.
Published: March 2024

Abstract
Hyperactive EGF receptor (EGFR) and mutant p53 are common genetic abnormalities driving the progression of non–small cell lung cancer (NSCLC), the leading cause of cancer deaths in the world. The Drosophila gene Dachshund (Dac) was originally cloned as an inhibitor of hyperactive EGFR alleles. Given the importance of EGFR signaling in lung cancer etiology, we examined the role of DACH1 expression in lung cancer development. DACH1 protein and mRNA expression was reduced in human NSCLC. Reexpression of DACH1 reduced NSCLC colony formation and tumor growth in vivo via p53. Endogenous DACH1 colocalized with p53 in a nuclear, extranucleolar location, and shared occupancy of −15% of p53-bound genes in ChIP sequencing. The C-terminus of DACH1 was necessary for direct p53 binding, contributing to the inhibition of colony formation and cell-cycle arrest. Expression of the stem cell factor SOX2 was repressed by DACH1, and SOX2 expression was inversely correlated with DACH1 in NSCLC. We conclude that DACH1 binds p53 to inhibit NSCLC cellular growth. Cancer Res; 73(11); 3262–74. ©2013 AACR.
Data from Cetuximab Response of Lung Cancer–Derived EGF Receptor Mutants Is Associated with Asymmetric Dimerization
Authors: Cho Jeonghee , Chen Liang , Sangji Naveen , Okabe Takafumi , Yonesaka Kimio , Francis Joshua M. , Flavin Richard J. , Johnson William , Kwon Jihyun , Yu Soyoung , Greulich Heidi , Johnson Bruce E. , Eck Michael J. , Jänne Pasi A. , Wong Kwok-Kin , Meyerson Matthew
Published: March 2024

Abstract
Kinase domain mutations of the EGF receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here, we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer–derived EGFR mutants. We show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. In addition, treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization-dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization-independent EGFR mutants. These data imply that different EGFR mutants show differential requirements for dimerization and that disruption of dimerization may be among the antitumor mechanisms of cetuximab. Cancer Res; 73(22); 6770–9. ©2013 AACR.
Data from Impact of Body Mass Index on the Risk of Colorectal Adenoma in a Metabolically Healthy Population
Authors: Yun Kyung Eun , Chang Yoosoo , Jung Hyun-Suk , Kim Chan-Won , Kwon Min-Jung , Park Sung Keun , Sung Eunju , Shin Hocheol , Park Hye Soon , Ryu Seungho
Published: March 2024

Abstract
Metabolically healthy obese (MHO) states exist that seem to be protected from cardiovascular risks. Although obesity is a risk factor for colorectal adenoma (CRA), there has yet to be any study of the risks of CRA in MHO individuals. In this study, we compared CRA prevalence in MHO individuals versus metabolically healthy individuals who were normal in weight. This cross-sectional study involved 18,085 Korean adults (39.1 ± 6.7 years) who had a health checkup including a colonoscopy. High-risk CRA was defined as any adenoma over 1 cm, 3 or more adenomas, adenoma with a villous component, or high-grade dysplasia. Multinomial logistic regression models were used to measure the associations between body mass index (BMI) and the risk of low-risk and high-risk CRA. Low-risk and high-risk CRA were present in 9.3% and 1.4% of the study population, respectively. After adjusting for age, sex, smoking, drinking, exercise, family history of colorectal cancer, education, and use of analgesic and aspirin, compared with normal healthy individuals, the prevalence of low-risk and high-risk CRA was increased in MHO individuals [OR = 1.44; 95% confidence interval (CI), 1.23–1.69 and OR = 1.62; 95% CI, 1.09–2.41, respectively]. In fully adjusted models, the prevalence of low-risk and high-risk CRA was associated with increasing categories of BMI in a dose–response manner (P for trend < 0.001 and 0.01, respectively). Thus, excess body weight, even in the absence of a metabolic unhealthy state, was found to be positively associated with increased presence of CRAs. Cancer Res; 73(13); 4020–7. ©2013 AACR.
Data from Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling
Authors: Kanda Rina , Kawahara Akihiko , Watari Kosuke , Murakami Yuichi , Sonoda Kahori , Maeda Masashi , Fujita Hideaki , Kage Masayoshi , Uramoto Hidetaka , Costa Carlota , Kuwano Michihiko , Ono Mayumi
Published: March 2024

Abstract
EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non–small cell lung cancers harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin β1, α2, and α5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin β1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin β1, α5, and/or α2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin β1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs. Cancer Res; 73(20); 6243–53. ©2013 AACR.
Data from Peroxiredoxin-2 Represses Melanoma Metastasis by Increasing E-Cadherin/β-Catenin Complexes in Adherens Junctions
Authors: Lee Doo Jae , Kang Dong Hoon , Choi Mina , Choi Yang Ji , Lee Joo Young , Park Joo Hyun , Park Yoon Jung , Lee Kyung Wha , Kang Sang Won
Published: March 2024

Abstract
In melanoma, transition to the vertical growth phase is the critical step in conversion to a deadly malignant disease. Here, we offer the first evidence that an antioxidant enzyme has a key role in this transition. We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells. Silencing Prx2 expression stimulated proliferation and migration, whereas ectopic expression of Prx2 produced the opposite effect. Mechanistic investigations indicated that Prx2 negatively regulated Src/ERK activation status, which in turn fortified adherens junctions function by increasing E-cadherin expression and phospho-Y654–dependent retention of β-catenin in the plasma membrane. In murine melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, the natural compound gliotoxin, which is known to exert a Prx-like activity, inhibited proliferation and migration as well as lung metastasis of Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key regulator of invasion and metastasis in melanoma, and also suggest a pharmacologic strategy to effectively decrease deadly malignant forms of this disease. Cancer Res; 73(15); 4744–57. ©2013 AACR.
Data from Chemoprevention of Prostate Cancer by d,l-Sulforaphane Is Augmented by Pharmacological Inhibition of Autophagy
Authors: Vyas Avani R. , Hahm Eun-Ryeong , Arlotti Julie A. , Watkins Simon , Stolz Donna Beer , Desai Dhimant , Amin Shantu , Singh Shivendra V.
Published: March 2024

Abstract
There is a preclinical evidence that the oral administration of d,l-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer [prostatic intraepithelial neoplasia (PIN)] and well-differentiated cancer (WDC) but not late-stage poorly differentiated cancer (PDC). Because SFN treatment induces cytoprotective autophagy in cultured human prostate cancer cells, the present study tested the hypothesis that chemopreventive efficacy of SFN could be augmented by the pharmacologic inhibition of autophagy using chloroquine (CQ). Incidence of PDC characterized by prostate weight of more than 1 g was significantly lower in the SFN + CQ group than in control (P = 0.004), CQ group (P = 0.026), or SFN group (P = 0.002 by Fisher exact test). Average size of the metastatic lymph node was lower by about 42% in the SFN + CQ group than in control (P = 0.043 by Wilcoxon test). On the other hand, the SFN + CQ combination was not superior to SFN alone with respect to inhibition of incidence or burden of microscopic PIN or WDC. SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN + CQ combination was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial–mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN + CQ exposure/response. This study offers a novel combination regimen for future clinical investigations for prevention of prostate cancer in humans. Cancer Res; 73(19); 5985–95. ©2013 AACR.
Data from Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells
Authors: Tai Lee-Hwa , de Souza Christiano Tanese , Bélanger Simon , Ly Lundi , Alkayyal Almohanad A. , Zhang Jiqing , Rintoul Julia L. , Ananth Abhirami A. , Lam Tiffany , Breitbach Caroline J. , Falls Theresa J. , Kirn David H. , Bell John C. , Makrigiannis Andrew P. , Auer Rebecca A.
Published: March 2024

Abstract
Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients. Cancer Res; 73(1); 97–107. ©2012 AACR.
Data from Epimorphin Is a Novel Regulator of the Progesterone Receptor Isoform-A
Authors: Bascom Jamie L. , Radisky Derek C. , Koh Eileen , Fata Jimmie E. , Lo Alvin , Mori Hidetoshi , Roosta Neda , Hirai Yohei , Bissell Mina J.
Published: March 2024

Abstract
Epimorphin/syntaxin-2 is a membrane-tethered protein localized extracellularly (Epim) and intracellularly (Stx-2). The extracellular form Epim stimulates morphogenic processes in a range of tissues, including in murine mammary glands where its overexpression in luminal epithelial cells is sufficient to drive hyperplasia and neoplasia. We analyzed WAP-Epim transgenic mice to gain insight into how Epim promotes malignancy. Ectopic overexpression of Epim during postnatal mammary gland development led to early side-branching onset, precocious bud formation, and increased proliferation of mammary epithelial cells. Conversely, peptide-based inhibition of Epim function reduced side branching. Because increased side branching and hyperplasia occurs similarly in mice upon overexpression of the progesterone receptor isoform-a (Pgr-a), we investigated whether Epim exhibits these phenotypes through Pgr modulation. Epim overexpression indeed led to a steep upregulation of both total Pgr mRNA and Pgr-a protein levels. Notably, the Pgr antagonist RU486 abrogated Epim-induced ductal side branching, mammary epithelial cell proliferation, and bud formation. Evaluation of Epim signaling in a three-dimensional ex vivo culture system showed that its action was dependent on binding to its extracellular receptor, integrin-αV, and on matrix metalloproteinase 3 activity downstream of Pgr-a. These findings elucidate a hitherto unknown transcriptional regulator of Pgr-a, and shed light on how overexpression of Epim leads to malignancy. Cancer Res; 73(18); 5719–29. ©2013 AACR.
Data from Pathway-Based Serum microRNA Profiling and Survival in Patients with Advanced Stage Non–Small Cell Lung Cancer
Authors: Wang Yan , Gu Jian , Roth Jack A. , Hildebrandt Michelle A.T. , Lippman Scott M. , Ye Yuanqing , Minna John D. , Wu Xifeng
Published: March 2024

Abstract
This study was designed to identify TGF-β signaling pathway-related serum microRNAs (miRNA) as predictors of survival in advanced non–small cell lung cancer (NSCLC). Serum samples from 391 patients with advanced NSCLC were collected before treatment. Global miRNA microarray expression profiling based on sera from four patients with good survival (>24 months) and four patients with poor survival (<6 months) was used to identify 140 highly expressed serum miRNAs, among which 35 miRNAs had binding sites within the 3′-untranslated regions of a panel of 11 genes in the TGF-β signaling pathway and were assayed by quantitative RT-PCR for their associations with survival in a training (n = 192) and testing set (n = 191). Out of the 35 miRNAs, survival analysis using Cox regression model identified 17 miRNAs significantly associated with 2-year patient survival. MiR-16 exhibited the most statistically significant association: high expression of miR-16 was associated with a significantly better survival [adjusted hazard ratio (HR) = 0.4, 95% confidence interval (CI): 0.3–0.5]. A combined 17-miRNA risk score was created that was able to identify patients at the highest risk of death. Those with a high-risk score had a 2.5-fold increased risk of death compared with those with a low risk score (95% CI: 1.8–3.4; P = 1.1 × 10−7). This increase in risk of death was corresponding to a 7.8-month decrease in median survival time (P = 9.5 × 10−14). Our results suggest that serum miRNAs could serve as predictors of survival for advanced NSCLC. Cancer Res; 73(15); 4801–9. ©2013 AACR.
Data from CX3CL1 Promotes Breast Cancer via Transactivation of the EGF Pathway
Authors: Tardáguila Manuel , Mira Emilia , García-Cabezas Miguel A. , Feijoo Anna M. , Quintela-Fandino Miguel , Azcoitia Iñigo , Lira Sergio A. , Mañes Santos
Published: March 2024

Abstract
Chemokines are relevant molecules in shaping the tumor microenvironment, although their contributions to tumorigenesis are not fully understood. We studied the influence of the chemokine CX3CL1/fractalkine in de novo breast cancer formation using HER2/neu transgenic mice. CX3CL1 expression was downmodulated in HER2/neu tumors, yet, paradoxically, adenovirus-mediated CX3CL1 expression in the tumor milieu enhanced mammary tumor numbers in a dose-dependent manner. Increased tumor multiplicity was not a consequence of CX3CL1-induced metastatic dissemination of the primary tumor, although CX3CL1 induced epithelial-to-mesenchymal transition in breast cancer cells in vitro. Instead, CX3CL1 triggered cell proliferation by induction of ErbB receptors through the proteolytic shedding of an ErbB ligand. This effect was important insofar as mammary tumorigenesis was delayed and tumor multiplicity was reduced by genetic deletion of CX3CL1 in HER2/neu mice, but not in polyoma middle T-antigen oncomice. Our findings support the conclusion that CX3CL1 acts as a positive modifier of breast cancer in concert with ErbB receptors. Cancer Res; 73(14); 4461–73. ©2013 AACR.
Data from Constitutive HER2 Signaling Promotes Breast Cancer Metastasis through Cellular Senescence
Authors: Angelini Pier Davide , Fluck Mariano F. Zacarias , Pedersen Kim , Parra-Palau Josep Lluís , Guiu Marc , Bernadó Morales Cristina , Vicario Rocio , Luque-García Antonio , Navalpotro Nerea Peiró , Giralt Jordi , Canals Francesc , Gomis Roger R. , Tabernero Josep , Baselga José , Villanueva Josep , Arribas Joaquín
Published: March 2024

Abstract
Senescence, a terminal cell proliferation arrest, can be triggered by oncogenes. Oncogene-induced senescence is classically considered a tumor defense barrier. However, several findings show that, under certain circumstances, senescent cells may favor tumor progression because of their secretory phenotype. Here, we show that the expression in different breast epithelial cell lines of p95HER2, a constitutively active fragment of the tyrosine kinase receptor HER2, results in either increased proliferation or senescence. In senescent cells, p95HER2 elicits a secretome enriched in proteases, cytokines, and growth factors. This secretory phenotype is not a mere consequence of the senescence status and requires continuous HER2 signaling to be maintained. Underscoring the functional relevance of the p95HER2-induced senescence secretome, we show that p95HER2-induced senescent cells promote metastasis in vivo in a non–cell-autonomous manner. Cancer Res; 73(1); 450–8. ©2012 AACR.
Data from A Comparative Genomic Approach for Identifying Synthetic Lethal Interactions in Human Cancer
Authors: Deshpande Raamesh , Asiedu Michael K. , Klebig Mitchell , Sutor Shari , Kuzmin Elena , Nelson Justin , Piotrowski Jeff , Ho Shin Seung , Yoshida Minoru , Costanzo Michael , Boone Charles , Wigle Dennis A. , Myers Chad L.
Published: March 2024

Abstract
Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We describe a comparative genomic strategy for identifying cancer-relevant synthetic lethal interactions whereby candidate interactions are prioritized on the basis of genetic interaction data available in yeast, followed by targeted testing of candidate interactions in human cell lines. As a proof of principle, we describe two novel synthetic lethal interactions in human cells discovered by this approach, one between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2. These results suggest therapeutic targets for cancers harboring mutations in SMARCB1 or ASPSCR1 and highlight the potential of a targeted, cross-species strategy for identifying synthetic lethal interactions relevant to human cancer. Cancer Res; 73(20); 6128–36. ©2013 AACR.
Data from miR145 Targets the SOX9/ADAM17 Axis to Inhibit Tumor-Initiating Cells and IL-6–Mediated Paracrine Effects in Head and Neck Cancer
Authors: Yu Cheng-Chia , Tsai Lo-Lin , Wang Mong-Lien , Yu Chuan-Hang , Lo Wen-Liang , Chang Yun-Ching , Chiou Guang-Yuh , Chou Ming-Yung , Chiou Shih-Hwa
Published: March 2024

Abstract
ALDH1+CD44+ cells are putative tumor-initiating cells (TIC) in head and neck squamous cell carcinomas (HNC). miR-145 regulates tumorigenicity in various cancers but the breadth of its mechanistic contributions and potential therapeutic applications are not completely known. Here, we report that ALDH1+CD44+-HNC cells express reduced levels of miR145. SPONGE-mediated inhibition of miR-145 (Spg-miR145) was sufficient to drive tumor-initiating characteristics in non-TICs/ALDH1−CD44-negative HNC cells. Mechanistic analyses identified SOX9 and ADAM17 as two novel miR145 targets relevant to this process. miR-145 expression repressed TICs in HNC in a manner associated with SOX9 interaction with the ADAM17 promoter, thereby activating ADAM17 expression. Notably, the SOX9/ADAM17 axis dominated the TIC-inducing activity of miR-145. Either miR-145 suppression or ADAM17 overexpression in non-TICs/ALDH1−CD44−-HNC cells increased expression and secretion of interleukin (IL)-6 and soluble-IL-6 receptor (sIL-6R). Conversely, conditioned medium from Spg-miR145–transfected non-TICs/ALDH1−CD44−-HNC cells was sufficient to confer tumor-initiating properties in non-TICs/ALDH1−CD44−-HNC and this effect could be abrogated by an IL-6–neutralizing antibody. We found that curcumin administration increased miR-145 promoter activity, thereby decreasing SOX9/ADAM17 expression and eliminating TICs in HNC cell populations. Delivery of lentivral-miR145 or orally administered curcumin blocked tumor progression in HNC-TICs in murine xenotransplant assays. Finally, immunohistochemical analyses of patient specimens confirmed that an miR-145low/SOX9high/ADAM17high phenotype correlated with poor survival. Collectively, our results show how miR-145 targets the SOX9/ADAM17 axis to regulate TIC properties in HNC, and how altering this pathway may partly explain the anticancer effects of curcumin. By inhibiting IL-6 and sIL-6R as downstream effector cytokines in this pathway, miR-145 seems to suppress a paracrine signaling pathway in the tumor microenvironment that is vital to maintain TICs in HNC. Cancer Res; 73(11); 3425–40. ©2013 AACR.
Data from TR3 Modulates Platinum Resistance in Ovarian Cancer
Authors: Wilson Andrew J. , Liu Annie Y. , Roland Joseph , Adebayo Oluwafunmilayo B. , Fletcher Sarah A. , Slaughter James C. , Saskowski Jeanette , Crispens Marta A. , Jones Howard W. , James Samuel , Fadare Oluwole , Khabele Dineo
Published: March 2024

Abstract
In metastatic ovarian cancer, resistance to platinum chemotherapy is common. Although the orphan nuclear receptor TR3 (nur77/NR4A1) is implicated in mediating chemotherapy-induced apoptosis in cancer cells, its role in ovarian cancer has not been determined. In an ovarian cancer tissue microarray, TR3 protein expression was elevated in stage I tumors, but downregulated in a significant subset of metastatic tumors. Moreover, TR3 expression was significantly lower in platinum-resistant tumors in patients with metastatic disease, and low TR3 staining was associated with poorer overall and progression-free survival. We have identified a direct role for TR3 in cisplatin-induced apoptosis in ovarian cancer cells. Nucleus-to-cytoplasm translocation of TR3 was observed in cisplatin-sensitive (OVCAR8, OVCAR3, and A2780PAR) but not cisplatin-resistant (NCI/ADR-RES and A2780CP20) ovarian cancer cells. Immunofluorescent analyses showed clear overlap between TR3 and mitochondrial Hsp60 in cisplatin-treated cells, which was associated with cytochrome c release. Ovarian cancer cells with stable shRNA- or transient siRNA-mediated TR3 downregulation displayed substantial reduction in cisplatin effects on apoptotic markers and cell growth in vitro and in vivo. Mechanistic studies showed that the cisplatin-induced cytoplasmic TR3 translocation required for apoptosis induction was regulated by JNK activation and inhibition of Akt. Finally, cisplatin resistance was partially overcome by ectopic TR3 overexpression and by treatment with the JNK activator anisomycin and Akt pathway inhibitor, wortmannin. Our results suggest that disruption of TR3 activity, via downregulation or nuclear sequestration, likely contributes to platinum resistance in ovarian cancer. Moreover, we have described a treatment strategy aimed at overcoming platinum resistance by targeting TR3. Cancer Res; 73(15); 4758–69. ©2013 AACR.
Data from Reg3β Deficiency Impairs Pancreatic Tumor Growth by Skewing Macrophage Polarization
Authors: Gironella Meritxell , Calvo Carlos , Fernández Anna , Closa Daniel , Iovanna Juan L. , Rosello-Catafau Joan , Folch-Puy Emma
Published: March 2024

Abstract
The lectin Reg3β provides crucial protection to various tissues against inflammation, a potential risk factor for pancreatic ductal adenocarcinoma. Reg3β is also overexpressed in serum and pancreatic juice from patients with this cancer, but its function in this context remains to be elucidated. In this study, we investigated the role of Reg3β in tumor development in an orthotopic mouse model of pancreatic cancer. Reg3β deletion in mice drastically impaired pancreatic tumor growth, correlating with decreased angiogenesis and increased apoptosis of tumor cells. Moreover, Reg3β deficiency resulted in an alteration of the tumoral immune microenvironment, reflected by a decrease in the M2/M1 ratio of tumor-associated macrophages and an upregulation of CD3+ cell infiltration. Addition of Reg3β to prestimulated RAW 264.7 or primary macrophages enhanced M2 polarization through the activation of STAT3 signaling pathway. Conditioned media from Reg3β-M2-polarized primary macrophages inhibited apoptosis and prolonged the viability of Panc02 tumor cells. Our studies reveal a novel role for Reg3β as a tumor promoter in pancreatic adenocarcinoma through the regulation of tumor stroma. Thus, inhibition of this protein may be a useful strategy in treatment of pancreatic cancer. Cancer Res; 73(18); 5682–94. ©2013 AACR.
Data from A Novel Model of Dormancy for Bone Metastatic Breast Cancer Cells
Authors: Marlow Rebecca , Honeth Gabriella , Lombardi Sara , Cariati Massimiliano , Hessey Sonya , Pipili Aikaterini , Mariotti Veronica , Buchupalli Bharath , Foster Katie , Bonnet Dominique , Grigoriadis Agamemnon , Rameshwar Pranela , Purushotham Anand , Tutt Andrew , Dontu Gabriela
Published: March 2024

Abstract
Mortality of patients with breast cancer is due overwhelmingly to metastatic spread of the disease. Although dissemination is an early event in breast cancer, extended periods of cancer cell dormancy can result in long latency of metastasis development. Deciphering the mechanisms underlying cancer cell dormancy and subsequent growth at the metastatic site would facilitate development of strategies to interfere with these processes. A challenge in this undertaking has been the lack of models for cancer cell dormancy. We have established novel experimental systems that model the bone microenvironment of the breast cancer metastatic niche. These systems are based on 3D cocultures of breast cancer cells with cell types predominant in bone marrow. We identified conditions in which cancer cells are dormant and conditions in which they proliferate. Dormant cancer cells were able to proliferate upon transfer into supportive microenvironment or upon manipulation of signaling pathways that control dormancy. These experimental systems will be instrumental for metastasis studies, particularly the study of cellular dormancy. Cancer Res; 73(23); 6886–99. ©2013 AACR.
Data from Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation
Authors: Pinho Filipa G. , Frampton Adam E. , Nunes Joao , Krell Jonathan , Alshaker Heba , Jacob Jimmy , Pellegrino Loredana , Roca-Alonso Laura , de Giorgio Alexander , Harding Victoria , Waxman Jonathan , Stebbing Justin , Pchejetski Dmitry , Castellano Leandro
Published: March 2024

Abstract
Sphingosine kinase 1 (SK1) plays an important role in estrogen-dependent breast tumorigenesis, but its regulation is poorly understood. A subset of microRNAs (miRNA, miR) is regulated by estrogen and contributes to cellular proliferation and cancer progression. Here, we describe that miR-515-5p is transcriptionally repressed by estrogen receptor α (ERα) and functions as a tumor suppressor in breast cancer. Its downregulation enhances cell proliferation and estrogen-dependent SK1 activity, mediated by a reduction of miR-515-5p posttranscriptional repression. Enforced expression of miR-515-5p in breast cancer cells causes a reduction in SK1 activity, reduced cell proliferation, and the induction of caspase-dependent apoptosis. Conversely, opposing effects occur with miR-515-5p inhibition and by SK1 silencing. Notably, we show that estradiol (E2) treatment downregulates miR-515-5p levels, whereas the antiestrogen tamoxifen causes a decrease in SK1, which is rescued by silencing miR-515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERα within its promoter. RNA-sequencing (RNA-Seq) analysis of breast cancer cells after overexpressing miR-515-5p indicates that it partly modulates cell proliferation by regulating the Wnt pathway. The clinical implications of this novel regulatory system are shown as miR-515-5p is significantly downregulated in ER-positive (n = 146) compared with ER-negative (n = 98) breast cancers. Overall, we identify a new link between ERα, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis. Cancer Res; 73(19); 5936–48. ©2013 AACR.
Data from Mathematical Modeling of Tumor Cell Proliferation Kinetics and Label Retention in a Mouse Model of Lung Cancer
Authors: Zheng Yanyan , Moore Helen , Piryatinska Alexandra , Solis Trinidad , Sweet-Cordero E. Alejandro
Published: March 2024

Abstract
Slowly cycling tumor cells that may be present in human tumors may evade cytotoxic therapies, which tend to be more efficient at destroying cells with faster growth rates. However, the proportion and growth rate of slowly cycling tumor cells is often unknown in preclinical model systems used for drug discovery. Here, we report a quantitative approach to quantitate slowly cycling malignant cells in solid tumors, using a well-established mouse model of Kras-induced lung cancer (KrasG12D/+). 5-Bromo-2-deoxyuridine (BrdUrd) was administered to tumor-bearing mice, and samples were collected at defined times during pulse and chase phases. Mathematical and statistical modeling of the label-retention data during the chase phase supported the existence of a slowly cycling label-retaining population in this tumor model and permitted the estimation of its proportion and proliferation rate within a tumor. The doubling time of the slowly cycling population was estimated at approximately 5.7 weeks, and this population represented approximately 31% of the total tumor cells in this model system. The mathematical modeling techniques implemented here may be useful in other tumor models where direct observation of cell-cycle kinetics is difficult and may help evaluate tumor cell subpopulations with distinct cell-cycling rates. Cancer Res; 73(12); 3525–33. ©2013 AACR.
Data from Requirements for Aurora-A in Tissue Regeneration and Tumor Development in Adult Mammals
Authors: Pérez de Castro Ignacio , Aguirre-Portolés Cristina , Fernández-Miranda Gonzalo , Cañamero Marta , Cowley Dale O. , Van Dyke Terry , Malumbres Marcos
Published: March 2024

Abstract
Aurora-A is a kinase involved in the formation and maturation of the mitotic spindle and chromosome segregation. This kinase is frequently overexpressed in human cancer, and its activity may confer resistance to antitumoral drugs such as Taxol. Inhibition of Aurora-A results in mitotic defects, and this kinase is considered as an attractive therapeutic target for cancer. Nevertheless, the specific requirements for this kinase in adult mammalian tissues remain unclear. Conditional genetic ablation of Aurora-A in adult tissues results in polyploid cells that display a DNA-damage–like response characterized by the upregulation of p53 and the cell-cycle inhibitor p21Cip1. This is accompanied by apoptotic, differentiation, or senescence markers in a tissue-specific manner. Therapeutic elimination of Aurora-A prevents the progression of skin and mammary gland tumors. However, this is not due to significant levels of apoptosis or senescence, but because Aurora-A–deficient tumors accumulate polyploid cells with limited proliferative potential. Thus, Aurora-A is required for tumor formation in vivo, and the differential response observed in various tissues might have relevant implications in current therapeutic strategies aimed at inhibiting this kinase in the treatment of human cancer. Cancer Res; 73(22); 6804–15. ©2013 AACR.
Data from EGFR-Activating Mutations Correlate with a Fanconi Anemia–like Cellular Phenotype That Includes PARP Inhibitor Sensitivity
Authors: Pfäffle Heike N. , Wang Meng , Gheorghiu Liliana , Ferraiolo Natalie , Greninger Patricia , Borgmann Kerstin , Settleman Jeffrey , Benes Cyril H. , Sequist Lecia V. , Zou Lee , Willers Henning
Published: March 2024

Abstract
In patients with lung cancer whose tumors harbor activating mutations in the EGF receptor (EGFR), increased responses to platinum-based chemotherapies are seen compared with wild-type cancers. However, the mechanisms underlying this association have remained elusive. Here, we describe a cellular phenotype of cross-linker sensitivity in a subset of EGFR-mutant lung cancer cell lines that is reminiscent of the defects seen in cells impaired in the Fanconi anemia pathway, including a pronounced G2–M cell-cycle arrest and chromosomal radial formation. We identified a defect downstream of FANCD2 at the level of recruitment of FAN1 nuclease and DNA interstrand cross-link (ICL) unhooking. The effect of EGFR mutation was epistatic with FANCD2. Consistent with the known role of FANCD2 in promoting RAD51 foci formation and homologous recombination repair (HRR), EGFR-mutant cells also exhibited an impaired RAD51 foci response to ICLs, but not to DNA double-strand breaks. EGFR kinase inhibition affected RAD51 foci formation neither in EGFR-mutant nor wild-type cells. In contrast, EGFR depletion or overexpression of mutant EGFR in wild-type cells suppressed RAD51 foci, suggesting an EGFR kinase-independent regulation of DNA repair. Interestingly, EGFR-mutant cells treated with the PARP inhibitor olaparib also displayed decreased FAN1 foci induction, coupled with a putative block in a late HRR step. As a result, EGFR-mutant lung cancer cells exhibited olaparib sensitivity in vitro and in vivo. Our findings provide insight into the mechanisms of cisplatin and PARP inhibitor sensitivity of EGFR-mutant cells, yielding potential therapeutic opportunities for further treatment individualization in this genetically defined subset of lung cancer. Cancer Res; 73(20); 6254–63. ©2013 AACR.
Data from c-Src Modulates Estrogen-Induced Stress and Apoptosis in Estrogen-Deprived Breast Cancer Cells
Authors: Fan Ping , Griffith Obi L. , Agboke Fadeke A. , Anur Pavana , Zou Xiaojun , McDaniel Russell E. , Creswell Karen , Kim Sung Hoon , Katzenellenbogen John A. , Gray Joe W. , Jordan V. Craig
Published: March 2024

Abstract
The emergence of anti-estrogen resistance in breast cancer is an important clinical phenomenon affecting long-term survival in this disease. Identifying factors that convey cell survival in this setting may guide improvements in treatment. Estrogen (E2) can induce apoptosis in breast cancer cells that have been selected for survival after E2 deprivation for long periods (MCF-7:5C cells), but the mechanisms underlying E2-induced stress in this setting have not been elucidated. Here, we report that the c-Src kinase functions as a key adapter protein for the estrogen receptor (ER, ESR1) in its activation of stress responses induced by E2 in MCF-7:5C cells. E2 elevated phosphorylation of c-Src, which was blocked by 4-hydroxytamoxifen (4-OHT), suggesting that E2 activated c-Src through the ER. We found that E2 activated the sensors of the unfolded protein response (UPR), IRE1α (ERN1) and PERK kinase (EIF2AK3), the latter of which phosphorylates eukaryotic translation initiation factor-2α (eIF2α). E2 also dramatically increased reactive oxygen species production and upregulated expression of heme oxygenase HO-1 (HMOX1), an indicator of oxidative stress, along with the central energy sensor kinase AMPK (PRKAA2). Pharmacologic or RNA interference–mediated inhibition of c-Src abolished the phosphorylation of eIF2α and AMPK, blocked E2-induced ROS production, and inhibited E2-induced apoptosis. Together, our results establish that c-Src kinase mediates stresses generated by E2 in long-term E2-deprived cells that trigger apoptosis. This work offers a mechanistic rationale for a new approach in the treatment of endocrine-resistant breast cancer. Cancer Res; 73(14); 4510–20. ©2013 AACR.
Data from The Exomes of the NCI-60 Panel: A Genomic Resource for Cancer Biology and Systems Pharmacology
Authors: Abaan Ogan D. , Polley Eric C. , Davis Sean R. , Zhu Yuelin J. , Bilke Sven , Walker Robert L. , Pineda Marbin , Gindin Yevgeniy , Jiang Yuan , Reinhold William C. , Holbeck Susan L. , Simon Richard M. , Doroshow James H. , Pommier Yves , Meltzer Paul S.
Published: March 2024

Abstract
The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. This panel has generated the most extensive cancer pharmacology database worldwide. In addition, these cell lines have been intensely investigated, providing a unique platform for hypothesis-driven research focused on enhancing our understanding of tumor biology. Here, we report a comprehensive analysis of coding variants in the NCI-60 panel of cell lines identified by whole exome sequencing, providing a list of possible cancer specific variants for the community. Furthermore, we identify pharmacogenomic correlations between specific variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin showing one of many ways the data could be used to validate and generate novel hypotheses for further investigation. As new cancer genes are identified through large-scale sequencing studies, the data presented here for the NCI-60 will be an invaluable resource for identifying cell lines with mutations in such genes for hypothesis-driven research. To enhance the utility of the data for the greater research community, the genomic variants are freely available in different formats and from multiple sources including the CellMiner and Ingenuity websites. Cancer Res; 73(14); 4372–82. ©2013 AACR.
Data from Nitric Oxide Production Upregulates Wnt/β-Catenin Signaling by Inhibiting Dickkopf-1
Authors: Du Qiang , Zhang Xinglu , Liu Quan , Zhang Xianghong , Bartels Christian E. , Geller David A.
Published: March 2024

Abstract
Nitric oxide signaling plays complex roles in carcinogenesis, in part, due to incomplete mechanistic understanding. In this study, we investigated our discovery of an inverse correlation in the expression of the inducible nitric oxide synthase (iNOS) and the Wnt/β-catenin regulator Dickkopf-1 (DKK1) in human cancer. In human tumors and animal models, induced nitric oxide synthesis increased Wnt/β-catenin signaling by negatively regulating DKK1 gene expression. Human iNOS (hiNOS) and DKK1 gene expression were inversely correlated in primary human colon and breast cancers, and in intestinal adenomas from Min (Apcmin/+) mice. Nitric oxide production by various routes was sufficient to decrease constitutive DKK1 expression, increasing Wnt/β-catenin signaling in colon and breast cancer cells and primary human hepatocytes, thereby activating the transcription of Wnt target genes. This effect could be reversed by RNA interference-mediated silencing of iNOS or treatment with iNOS inhibitors, which restored DKK1 expression and its inhibitory effect on Wnt signaling. Taken together, our results identify a previously unrecognized mechanism through which the nitric oxide pathway promotes cancer by unleashing Wnt/β-catenin signaling. These findings further the evidence that nitric oxide promotes human cancer and deepens insights in the complex control Wnt/β-catenin signaling during carcinogenesis. Cancer Res; 73(21); 6526–37. ©2013 AACR.
Data from Conditional Loss of ErbB3 Delays Mammary Gland Hyperplasia Induced by Mutant PIK3CA without Affecting Mammary Tumor Latency, Gene Expression, or Signaling
Authors: Young Christian D. , Pfefferle Adam D. , Owens Philip , Kuba María G. , Rexer Brent N. , Balko Justin M. , Sánchez Violeta , Cheng Hailing , Perou Charles M. , Zhao Jean J. , Cook Rebecca S. , Arteaga Carlos L.
Published: March 2024

Abstract
Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CAH1047R-expressing tumors. However, the p110α-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110α and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CAH1047R. These data suggest that PIK3CAH1047R-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110α and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations. Cancer Res; 73(13); 4075–85. ©2013 AACR.