bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from The Human WRN and BLM RecQ Helicases Differentially Regulate Cell Proliferation and Survival after Chemotherapeutic DNA Damage
Authors: Mao Frances J. , Sidorova Julia M. , Lauper Julia M. , Emond Mary J. , Monnat Raymond J.
Published: March 2023

Abstract
Loss-of-function mutations in the human RecQ helicase genes WRN and BLM respectively cause the genetic instability/cancer predisposition syndromes Werner syndrome and Bloom syndrome. To identify common and unique functions of WRN and BLM, we systematically analyzed cell proliferation, cell survival, and genomic damage in isogenic cell lines depleted of WRN, BLM, or both proteins. Cell proliferation and survival were assessed before and after treatment with camptothecin, cis-diamminedichloroplatinum(II), hydroxyurea, or 5-fluorouracil. Genomic damage was assessed, before and after replication arrest, by γ-H2AX staining, which was quantified at the single-cell level by flow cytometry. Cell proliferation was affected strongly by the extent of WRN and/or BLM depletion, and more strongly by BLM than by WRN depletion (P = 0.005). The proliferation of WRN/BLM-codepleted cells, in contrast, did not differ from BLM-depleted cells (P = 0.34). BLM-depleted and WRN/BLM-codepleted cells had comparably impaired survival after DNA damage, whereas WRN-depleted cells displayed a distinct pattern of sensitivity to DNA damage. BLM-depleted and WRN/BLM-codepleted cells had similar, significantly higher γ-H2AX induction levels than did WRN-depleted cells. Our results provide new information on the role of WRN and BLM in determining cell proliferation, cell survival, and genomic damage after chemotherapeutic DNA damage or replication arrest. We also provide new information on functional redundancy between WRN and BLM. These results provide a strong rationale for further developing WRN and BLM as biomarkers of tumor chemotherapeutic responsiveness. Cancer Res; 70(16); 6548–55. ©2010 AACR.
Data from Distinct Genomic Alterations in Prostate Cancers in Chinese and Western Populations Suggest Alternative Pathways of Prostate Carcinogenesis
Authors: Mao Xueying , Yu Yongwei , Boyd Lara K. , Ren Guoping , Lin Dongmei , Chaplin Tracy , Kudahetti Sakunthala C. , Stankiewicz Elzbieta , Xue Liyan , Beltran Luis , Gupta Manu , Oliver R. Tim D. , Lemoine Nick R. , Berney Daniel M. , Young Bryan D. , Lu Yong-Jie
Published: March 2023

Abstract
Prostate cancer is significantly more common in Western men than in Asian men, but the basis for this difference remains unknown. Because genomic studies of Asian prostate cancer are very limited, we used a genome-wide approach to reveal the genomic alterations in Chinese prostate cancers. We found a significant reduction in the frequency of certain somatic genomic changes that are commonly found in Western prostate cancers, including the 21q22.2-22.3 deletion, which involves the TMPRSS2:ERG fusion gene, and 10q deletion, which causes PTEN inactivation. Array results were confirmed by PCR-based molecular copy-number counting in selected samples. The different frequencies of these genomic changes were further evaluated by fluorescent in situ hybridization and immunohistochemistry analyses of tissue microarray samples. These alterations might be key genetic changes underlying the regional/ethnic difference in clinical incidence and might be induced by specific environmental and/or genetic risk factors that Western men are exposed to. Our findings suggest that tumors arise in Western and Chinese populations by alternative pathogenetic mechanisms. Cancer Res; 70(13); 5207–12. ©2010 AACR.
Data from Confounding Effects in “A Six-Gene Signature Predicting Breast Cancer Lung Metastasis”: Reply
Authors: Driouch Keltouma , Bonin Florian , Sin Soraya , Clairac Géraldine , Lidereau Rosette
Published: March 2023

Abstract
Molecular signatures have begun to elucidate the biological and molecular mechanisms underlying the phenotypic diversity of breast tumors. Breast tumors are characterized by five different molecular subtypes that are associated with distinct clinical outcomes in terms of prognosis, treatment response, and site of relapse. In particular, the basal-like and luminal B subtypes of tumors are more aggressive and have a higher tendency to metastasize to the lung than do the other subtypes. Given this difference in metastatic profiles of breast tumors, the six-gene signature (6GS) that we showed to be predictive of lung relapse was reexamined in the context of the tumor subtypes. This first analysis suggested that the 6GS is a surrogate for molecular subtype, discriminating basal-like tumors rather than tumors that metastasize to the lung. Here, we show that the 6GS discriminates the two overlapping features, the basal-like subtype and the tendency to metastasize to the lung. Nevertheless, the 6GS predicts lung metastases of breast tumors independent of the molecular subtypes. [Cancer Res 2009;69(24):9507–11]
Data from Deficiency of pRb Family Proteins and p53 in Invasive Urothelial Tumorigenesis
Authors: He Feng , Mo Lan , Zheng Xiao-Yong , Hu Changkun , Lepor Herbert , Lee Eva Y-H.P. , Sun Tung-Tien , Wu Xue-Ru
Published: March 2023

Abstract
Defects in pRb tumor suppressor pathway occur in ∼50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression. [Cancer Res 2009;69(24):9413–21]
Data from Aurora B–Mediated Phosphorylation of RASSF1A Maintains Proper Cytokinesis by Recruiting Syntaxin16 to the Midzone and Midbody
Authors: Song Su Jung , Kim Soon Jung , Song Min Sup , Lim Dae-Sik
Published: March 2023

Abstract
Aurora B is critically involved in ensuring proper cytokinesis and maintaining genomic stability. The tumor suppressor RASSF1A regulates cell cycle progression by regulating mitotic progression, G1-S transition, and microtubule stability. We previously reported that both Aurora A and Aurora B phosphorylate RASSF1A, and showed that phosphorylation of RASSF1A by Aurora A blocks the inhibitory function of RASSF1A toward anaphase-promoting complex-Cdc20. However, the role of Aurora B–mediated RASSF1A phosphorylation remains unknown. Here, we show that phosphorylation of RASSF1A on Ser203 by Aurora B during late mitosis has a critical role in regulating cytokinesis. Notably, RASSF1A interacts with Syntaxin16, a member of the t-SNARE family, at the midzone and midbody during late mitosis. Aurora B is required for this interaction and for the subsequent recruitment of Syntaxin16 to the midzone and midbody, a prerequisite for the successful completion of cytokinesis. Furthermore, Aurora B depletion results in a failure of Syntaxin16 to properly localize to the midzone and midbody, a mislocalization that was prevented by overexpression of the phosphomimetic RASSF1A (S203D) mutant. Finally, either depletion of Syntaxin16 or expression of the nonphosphorylatable RASSF1A (S203A) mutant results in cytokinesis defects. Our findings implicate Aurora B–mediated phosphorylation of RASSF1A in the regulation of cytokinesis. [Cancer Res 2009;69(22):8540–4]
Data from Activation of FOXO3a Is Sufficient to Reverse Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor Chemoresistance in Human Cancer
Authors: Yang Jer-Yen , Chang Chun-Ju , Xia Weiya , Wang Yan , Wong Kwok-Kin , Engelman Jeffrey A. , Du Yi , Andreeff Michael , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: March 2023

Abstract
Drug resistance is a central challenge of cancer therapy that ultimately leads to treatment failure. In this study, we characterized a mechanism of drug resistance that arises to AZD6244, an established mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitor currently being evaluated in cancer clinical trials. AZD6244 enhanced the expression of transcription factor FOXO3a, which suppressed cancer cell proliferation. In AZD6244-resistant cancer cells, we observed the impaired nuclear localization of FOXO3a, reduced FOXO3a-mediated transcriptional activity, and decreased the expression of FOXO3a target gene Bim after cell treatment with AZD6244. Resistant cells could be sensitized by phosphoinositide 3-kinase (PI3K)/AKT inhibitors, which are known to enhance FOXO3a nuclear translocation. Our findings define FOXO3a as candidate marker to predict the clinical efficacy of AZD6244. Furthermore, they suggest a mechanism of resistance to MEK inhibitors that may arise in the clinic yet can be overcome by cotreatment with PI3K/AKT inhibitors. Cancer Res; 70(11); 4709–18. ©2010 AACR.
Data from E-Cadherin/p120-Catenin and Tetraspanin Co-029 Cooperate for Cell Motility Control in Human Colon Carcinoma
Authors: Greco Céline , Bralet Marie-Pierre , Ailane Naouel , Dubart-Kupperschmitt Anne , Rubinstein Eric , Le Naour François , Boucheix Claude
Published: March 2023

Abstract
Tumor invasion and metastasis are major obstacles to clinical treatment that rely on cell migration. Here, we elucidate a mechanism of colon carcinoma cell migration that is supported by the cell surface tetraspanin Co-029 (tspan8), which is known to favor tumor progression and metastasis. This mechanism is unmasked by silencing of E-cadherin or its associated adapter molecule p120-catenin (p120ctn), and it involves a switch in signaling between the collagen-binding integrins α1β1 and α2β1. Direct interaction between E-cadherin and Co-029 was documented by chemical cross-linking and immunohistologic analysis of colon carcinomas. High expression of Co-029 and cytoplasmic delocalization of p120ctn were each associated with poor prognosis. Cell motility was reduced severely by antibody-mediated disruption of Co-029 only when p120ctn was silenced, suggesting that tumor progression may be hindered by Co-029 targeting. Our findings define a function for tetraspanin Co-029 as a modifier of cancer cell motility and reveal an adhesion signaling network implicated in progression and metastasis. Cancer Res; 70(19); 7674–83. ©2010 AACR.
Data from Vitamin D Deficiency Promotes Human Breast Cancer Growth in a Murine Model of Bone Metastasis
Authors: Ooi Li Laine , Zhou Hong , Kalak Robert , Zheng Yu , Conigrave Arthur D. , Seibel Markus J. , Dunstan Colin R.
Published: March 2023

Abstract
Vitamin D exerts antiproliferative, prodifferentiation, and proapoptotic effects on nonclassic target tissues such as breast. Blood levels of 25-hydroxyvitamin D [25(OH)D], the most sensitive indicator of vitamin D status, are inversely correlated with breast cancer risk; however, a causal relationship between vitamin D deficiency and breast cancer growth in bone has not been assessed. We examined the effect of vitamin D deficiency on the intraskeletal growth of the human breast cancer cell line MDA-MB-231-TxSA in a murine model of malignant bone lesions. Subsets of mice were treated concurrently with osteoprotegerin (OPG) to abrogate bone resorption. Outcomes were assessed by repeated radiographic and end-point micro–computed tomography and histologic analyses. Mice weaned onto a vitamin D–free diet developed vitamin D deficiency within 4 weeks [mean ± SE serum 25(OH)D: 11.5 ± 0.5 nmol/L], which was sustained throughout the study and was associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D–deficient than in vitamin D–sufficient mice after 2 weeks (radiographic osteolysis: +121.5%; histologic tumor area: +314%; P < 0.05). Although OPG treatment reduced the size of radiographic osteolyses and tumor area in both groups, tumors remained larger in OPG-treated vitamin D–deficient compared with OPG-treated vitamin D–sufficient mice (0.53 ± 0.05 mm2 versus 0.19 ± 0.05 mm2; P < 0.05). We conclude that vitamin D deficiency promotes the growth of human breast cancer cells in the bones of nude mice. These effects are partly mediated through secondary changes in the bone microenvironment, along with direct effects of vitamin D on tumor growth. Cancer Res; 70(5); 1835–44
Data from Antibody-Dependent Natural Killer Cell–Mediated Cytotoxicity Engendered by a Kinase-Inactive Human HER2 Adenovirus-Based Vaccination Mediates Resistance to Breast Tumors
Authors: Triulzi Chiara , Vertuani Simona , Curcio Claudia , Antognoli Agnese , Seibt Josef , Akusjärvi Göran , Wei Wei-Zen , Cavallo Federica , Kiessling Rolf
Published: March 2023

Abstract
Cancer vaccines may have applications in the therapy and prevention of mammary carcinoma. To investigate such applications, we constructed a recombinant adenoviral vaccine expressing a kinase-inactive mutant form of human HER2 and introduced this into BALB/c wild-type (WT) or HER2 transgenic mice. Here, we report contributions by antibody responses and natural killer (NK) cells in tumor protection in this model. One i.p. vaccination protected WT mice from the HER2-expressing mouse carcinoma D2F2/E2. Half of the HER2 transgenic mice were protected fully and long term after preventive vaccination. Tumor growth in mice that eventually developed neoplastic lesions was delayed. Protection in WT and HER2 transgenic mice was associated with high or low levels of IgG2a antibodies, respectively, whereas CTLs were observed in WT but not in HER2 transgenic mice. Depleting CD4+ or CD8+ cells in vaccinated WT mice had limited effects, suggesting that protection was largely independent of CD4+ or CD8+ T cells. In contrast, antibody-mediated tumor rejection seemed to contribute significantly based on a loss of protection in mice deficient for Fc-γ RI/III or B cells. Further, a role for antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells was indicated by evidence that vaccine protection could be abolished by in vivo depletion of NK cells. Lastly, NK cells and immune sera purified from WT or HER2 transgenic mice exhibited efficient ADCC of HER2-expressing tumor cells in vitro. Our findings define a critical requirement for NK cells in vaccine-induced protection against HER2-expressing tumors. Cancer Res; 70(19); 7431–41. ©2010 AACR.
Data from Endothelial Cell-Initiated Signaling Promotes the Survival and Self-Renewal of Cancer Stem Cells
Authors: Krishnamurthy Sudha , Dong Zhihong , Vodopyanov Dmitry , Imai Atsushi , Helman Joseph I. , Prince Mark E. , Wicha Max S. , Nör Jacques E.
Published: March 2023

Abstract
Recent studies have demonstrated that cancer stem cells play an important role in the pathobiology of head and neck squamous cell carcinomas (HNSCC). However, little is known about functional interactions between head and neck cancer stem-like cells (CSC) and surrounding stromal cells. Here, we used aldehyde dehydrogenase activity and CD44 expression to sort putative stem cells from primary human HNSCC. Implantation of 1,000 CSC (ALDH+CD44+Lin−) led to tumors in 13 (out of 15) mice, whereas 10,000 noncancer stem cells (ALDH−CD44−Lin−) resulted in 2 tumors in 15 mice. These data demonstrated that ALDH and CD44 select a subpopulation of cells that are highly tumorigenic. The ability to self-renew was confirmed by the observation that ALDH+CD44+Lin− cells sorted from human HNSCC formed more spheroids (orospheres) in 3-D agarose matrices or ultra-low attachment plates than controls and were serially passaged in vivo. We observed that approximately 80% of the CSC were located in close proximity (within 100-μm radius) of blood vessels in human tumors, suggesting the existence of perivascular niches in HNSCC. In vitro studies demonstrated that endothelial cell-secreted factors promoted self-renewal of CSC, as demonstrated by the upregulation of Bmi-1 expression and the increase in the number of orospheres as compared with controls. Notably, selective ablation of tumor-associated endothelial cells stably transduced with a caspase-based artificial death switch (iCaspase-9) caused a marked reduction in the fraction of CSC in xenograft tumors. Collectively, these findings indicate that endothelial cell-initiated signaling can enhance the survival and self-renewal of head and neck CSC. Cancer Res; 70(23); 9969–78. ©2010 AACR.
Data from Optical Detection of Buccal Epithelial Nanoarchitectural Alterations in Patients Harboring Lung Cancer: Implications for Screening
Authors: Roy Hemant K. , Subramanian Hariharan , Damania Dhwanil , Hensing Thomas A. , Rom William N. , Pass Harvey I. , Ray Daniel , Rogers Jeremy D. , Bogojevic Andrej , Shah Maitri , Kuzniar Tomasz , Pradhan Prabhakar , Backman Vadim
Published: March 2023

Abstract
We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (Ld), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non–small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs. Cancer Res; 70(20); 7748–54. ©2010 AACR.
Data from Protein Kinase D1 Suppresses Epithelial-to-Mesenchymal Transition through Phosphorylation of Snail
Authors: Du Cheng , Zhang Chuanyou , Hassan Sazzad , Biswas Md. Helal Uddin , Balaji K.C.
Published: March 2023

Abstract
Cancer cells undergo epithelial-mesenchymal transition (EMT) as a program of increased invasion and metastasis during cancer progression. Here, we report that a novel regulator of EMT in cancer cells is protein kinase D1 (PKD1), which is downregulated in advanced prostate, breast, and gastric cancers. Ectopic reexpression of PKD1 in metastatic prostate cancer cells reversibly suppressed expression of mesenchyme-specific genes and increased epithelial markers such as E-cadherin, whereas small interfering RNA–mediated knockdown of PKD1 increased expression of mesenchyme markers. Further, PKD1 inhibited tumor growth and metastasis in a tumor xenograft model. PKD1 phosphorylates Ser11 (S11) on transcription factor Snail, a master EMT regulator and repressor of E-cadherin expression, triggering nuclear export of Snail via 14-3-3σ binding. Snail S11 mutation causes acquisition of mesenchymal traits and expression of stem cell markers. Together, our results suggest that PKD1 functions as a tumor and metastasis suppressor, at least partly by regulating Snail-mediated EMT, and that loss of PKD1 may contribute to acquisition of an aggressive malignant phenotype. Cancer Res; 70(20); 7810–9. ©2010 AACR.
Data from Altered TGF-β Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis
Authors: Franco Omar E. , Jiang Ming , Strand Douglas W. , Peacock James , Fernandez Suzanne , Jackson Roger S. , Revelo Monica P. , Bhowmick Neil A. , Hayward Simon W.
Published: March 2023

Abstract
Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells. Cancer Res; 71(4); 1272–81. ©2011 AACR.
Data from Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry
Authors: Cai Qiuyin , Wen Wanqing , Qu Shimian , Li Guoliang , Egan Kathleen M. , Chen Kexin , Deming Sandra L. , Shen Hongbing , Shen Chen-Yang , Gammon Marilie D. , Blot William J. , Matsuo Keitaro , Haiman Christopher A. , Khoo Ui Soon , Iwasaki Motoki , Santella Regina M. , Zhang Lina , Fair Alecia Malin , Hu Zhibin , Wu Pei-Ei , Signorello Lisa B. , Titus-Ernstoff Linda , Tajima Kazuo , Henderson Brian E. , Chan Kelvin Y.K. , Kasuga Yoshio , Newcomb Polly A. , Zheng Hong , Cui Yong , Wang Furu , Shieh Ya-Lan , Iwata Hiroji , Le Marchand Loic , Chan Sum Yin , Shrubsole Martha J. , Trentham-Dietz Amy , Tsugane Shoichiro , Garcia-Closas Montserrat , Long Jirong , Li Chun , Shi Jiajun , Huang Bo , Xiang Yong-Bing , Gao Yu-Tang , Lu Wei , Shu Xiao-Ou , Zheng Wei
Published: March 2023

Abstract
We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of more than 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95% CI) = 1.30 (1.22–1.38) and 1.64 (1.50–1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10−30], Japanese women [ORs (95% CI) = 1.31 (1.13–1.52) and 1.37 (1.06–1.76), P for trend = 2.51 × 10−4], and European-ancestry American women [ORs (95% CI) = 1.07 (0.99–1.16) and 1.18 (1.04–1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95% CI) = 0.81 (0.63–1.06) and 0.85 (0.65–1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027]. In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high linkage disequilibrium with rs2046210 in Chinese (r2 = 0.91) and European-ancestry (r2 = 0.83) populations, but not in Africans (r2 = 0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region. Cancer Res; 71(4); 1344–55. ©2011 AACR.
Data from Pten Loss and RAS/MAPK Activation Cooperate to Promote EMT and Metastasis Initiated from Prostate Cancer Stem/Progenitor Cells
Authors: Mulholland David J. , Kobayashi Naoko , Ruscetti Marcus , Zhi Allen , Tran Linh M. , Huang Jiaoti , Gleave Martin , Wu Hong
Published: March 2023

Abstract
PTEN loss or PI3K/AKT signaling pathway activation correlates with human prostate cancer progression and metastasis. However, in preclinical murine models, deletion of Pten alone fails to mimic the significant metastatic burden that frequently accompanies the end stage of human disease. To identify additional pathway alterations that cooperate with PTEN loss in prostate cancer progression, we surveyed human prostate cancer tissue microarrays and found that the RAS/MAPK pathway is significantly elevated in both primary and metastatic lesions. In an attempt to model this event, we crossed conditional activatable K-rasG12D/WT mice with the prostate conditional Pten deletion model. Although RAS activation alone cannot initiate prostate cancer development, it significantly accelerated progression caused by PTEN loss, accompanied by epithelial-to-mesenchymal transition (EMT) and macrometastasis with 100% penetrance. A novel stem/progenitor subpopulation with mesenchymal characteristics was isolated from the compound mutant prostates, which was highly metastatic upon orthotopic transplantation. Importantly, inhibition of RAS/MAPK signaling by PD325901, a mitogen–activated protein (MAP)–extracellular signal–regulated (ER) kinase (MEK) inhibitor, significantly reduced the metastatic progression initiated from transplanted stem/progenitor cells. Collectively, our findings indicate that activation of RAS/MAPK signaling serves as a potentiating second hit to alteration of the PTEN/PI3K/AKT axis, and cotargeting both the pathways is highly effective in preventing the development of metastatic prostate cancers. Cancer Res; 72(7); 1878–89. ©2012 AACR.
Data from An NQO1 Substrate with Potent Antitumor Activity That Selectively Kills by PARP1-Induced Programmed Necrosis
Authors: Huang Xiumei , Dong Ying , Bey Erik A. , Kilgore Jessica A. , Bair Joseph S. , Li Long-Shan , Patel Malina , Parkinson Elizabeth I. , Wang Yiguang , Williams Noelle S. , Gao Jinming , Hergenrother Paul J. , Boothman David A.
Published: March 2023

Abstract
Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+/ATP depletion that stimulate Ca2+–dependent programmed necrosis, unique to this new class of NQO1 “bioactivated” drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1− cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers. Cancer Res; 72(12); 3038–47. ©2012 AACR.
Data from Extensive Promoter DNA Hypermethylation and Hypomethylation Is Associated with Aberrant MicroRNA Expression in Chronic Lymphocytic Leukemia
Authors: Baer Constance , Claus Rainer , Frenzel Lukas P. , Zucknick Manuela , Park Yoon Jung , Gu Lei , Weichenhan Dieter , Fischer Martina , Pallasch Christian Philipp , Herpel Esther , Rehli Michael , Byrd John C. , Wendtner Clemens-Martin , Plass Christoph
Published: March 2023

Abstract
Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). However, an understanding of the mechanisms that cause aberrant miRNA transcriptional control is lacking. In this study, we comprehensively investigated the role and extent of miRNA epigenetic regulation in CLL. Genome-wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed global DNA methylation patterns upstream of miRNA sequences that distinguished malignant from healthy cells and identified putative miRNA promoters. Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA hypomethylation accounted for more than 60% of all aberrant promoter-associated DNA methylation in CLL, and promoter DNA hypomethylation was restricted to well-defined regions. Individual hyper- and hypomethylated promoters allowed discrimination of CLL samples from healthy controls. Promoter DNA methylation patterns were confirmed in an independent patient cohort, with 11 miRNAs consistently showing an inverse correlation between DNA methylation status and expression level. Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL. Cancer Res; 72(15); 3775–85. ©2012 AACR.
Data from Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo
Authors: Hamaï Ahmed , Pignon Pascale , Raimbaud Isabelle , Duperrier-Amouriaux Karine , Senellart Hélène , Hiret Sandrine , Douillard Jean-Yves , Bennouna Jaafar , Ayyoub Maha , Valmori Danila
Published: March 2023

Abstract
The role of TH17 cells in cancer is being investigated, but the existence of tumor antigen–specific TH17 cells has yet to be ascertained. Here, we report the first description of a spontaneous TH17 (IL-17+) response to the important tumor antigen MAGE-A3, which occurred concurrently with a TH1 (IFN-γ+) response in a lung cancer patient. MAGE-A3–specific interleukin (IL)-17+ T cells were mainly CCR7+ central memory T cells, whereas IFN-γ+ cells were enriched for CCR7− effector memory T cells. An assessment of the fine specificity of antigen recognition by these T cells indicated that the CCR6+CCR4+ and CCR6+CXCR3+ fractions contained the same TH17/TH1 population at early and late differentiation stages, respectively, whereas the CCR6−CXCR3+ fraction contained a distinct TH1 population. These findings are important because they suggest a differentiation model in which tumor antigen–specific CD4+ T cells that are primed under TH17 polarizing conditions will progressively convert into IFN-γ–secreting cells in vivo as they differentiate into effector T cells that can effectively attack tumors. Cancer Res; 72(5); 1059–63. ©2012 AACR.
Data from Loss of PPP2R2A Inhibits Homologous Recombination DNA Repair and Predicts Tumor Sensitivity to PARP Inhibition
Authors: Kalev Peter , Simicek Michal , Vazquez Iria , Munck Sebastian , Chen Liping , Soin Thomas , Danda Natasha , Chen Wen , Sablina Anna
Published: March 2023

Abstract
Reversible phosphorylation plays a critical role in DNA repair. Here, we report the results of a loss-of-function screen that identifies the PP2A heterotrimeric serine/threonine phosphatases PPP2R2A, PPP2R2D, PPP2R5A, and PPP2R3C in double-strand break (DSB) repair. In particular, we found that PPP2R2A-containing complexes directly dephosphorylated ATM at S367, S1893, and S1981 to regulate its retention at DSB sites. Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2, resulting in G1 to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51. In tumor cells, blocking PPP2R2A thereby impaired the high-fidelity homologous recombination repair pathway and sensitized cells to small-molecule inhibitors of PARP. We found that PPP2R2A was commonly downregulated in non–small cell lung carcinomas, suggesting that PPP2R2A status may serve as a marker to predict therapeutic efficacy to PARP inhibition. In summary, our results deepen understanding of the role of PP2A family phosphatases in DNA repair and suggest PPP2R2A as a marker for PARP inhibitor responses in clinic. Cancer Res; 72(24); 6414–24. ©2012 AACR.
Data from Autophagy Control by the VEGF-C/NRP-2 Axis in Cancer and Its Implication for Treatment Resistance
Authors: Stanton Marissa J. , Dutta Samikshan , Zhang Heyu , Polavaram Navatha S. , Leontovich Alexey A. , Hönscheid Pia , Sinicrope Frank A. , Tindall Donald J. , Muders Michael H. , Datta Kaustubh
Published: March 2023

Abstract
A major contributor to cancer mortality is recurrence and subsequent metastatic transformation following therapeutic intervention. Therefore, in order to develop new treatment modalities and improve the efficacy of current ones, it is important to understand the molecular mechanisms that promote resistance to therapy in cancer cells. One pathway contributing to therapy resistance is autophagy, a self-digestive process that can eliminate unnecessary or damaged organelles to protect cancer cells from death. We have found that the VEGF-C/NRP-2 axis is involved in the activation of autophagy, which helps cancer cell survival following treatment. Inhibition of mTOR complex 1 activity by this axis is the underlying mechanism for the activation of autophagy. Furthermore, we identified two VEGF-C/NRP-2-regulated genes, LAMP-2 and WDFY-1, that have previously been suggested to participate in autophagy and vesicular trafficking. Upregulation of WDFY-1 following VEGF-C or NRP-2 depletion contributes to cytotoxic drug-mediated cell death. Together, these data suggest a link between the VEGF-C/NRP-2 axis and cancer cell survival despite the presence of chemotherapy-induced stress. Effective targeting of this pathway may lead to the development of new cancer therapies. Cancer Res; 73(1); 160–71. ©2012 AACR.
Data from Dysregulated Hematopoiesis Caused by Mammary Cancer Is Associated with Epigenetic Changes and Hox Gene Expression in Hematopoietic Cells
Authors: Sio Alexander , Chehal Manreet K. , Tsai Kevin , Fan Xueling , Roberts Morgan E. , Nelson Brad H. , Grembecka Jolanta , Cierpicki Tomasz , Krebs Danielle L. , Harder Kenneth W.
Published: March 2023

Abstract
Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes. Cancer Res; 73(19); 5892–904. ©2013 AACR.
Data from The Role of Cell Density and Intratumoral Heterogeneity in Multidrug Resistance
Authors: Lavi Orit , Greene James M. , Levy Doron , Gottesman Michael M.
Published: March 2023

Abstract
Recent data have demonstrated that cancer drug resistance reflects complex biologic factors, including tumor heterogeneity, varying growth, differentiation, apoptosis pathways, and cell density. As a result, there is a need to find new ways to incorporate these complexities in the mathematical modeling of multidrug resistance. Here, we derive a novel structured population model that describes the behavior of cancer cells under selection with cytotoxic drugs. Our model is designed to estimate intratumoral heterogeneity as a function of the resistance level and time. This updated model of the multidrug resistance problem integrates both genetic and epigenetic changes, density dependence, and intratumoral heterogeneity. Our results suggest that treatment acts as a selection process, whereas genetic/epigenetic alteration rates act as a diffusion process. Application of our model to cancer treatment suggests that reducing alteration rates as a first step in treatment causes a reduction in tumor heterogeneity and may improve targeted therapy. The new insight provided by this model could help to dramatically change the ability of clinical oncologists to design new treatment protocols and analyze the response of patients to therapy. Cancer Res; 73(24); 7168–75. ©2013 AACR.
Data from Cell Fate Factor DACH1 Represses YB-1–Mediated Oncogenic Transcription and Translation
Authors: Wu Kongming , Chen Ke , Wang Chenguang , Jiao Xuanmao , Wang Liping , Zhou Jie , Wang Jing , Li Zhiping , Addya Sankar , Sorensen Poul H. , Lisanti Michael P. , Quong Andrew , Ertel Adam , Pestell Richard G.
Published: March 2023

Abstract
The epithelial–mesenchymal transition (EMT) enhances cellular invasiveness and confers tumor cells with cancer stem cell–like characteristics, through transcriptional and translational mechanisms. The mechanisms maintaining transcriptional and translational repression of EMT and cellular invasion are poorly understood. Herein, the cell fate determination factor Dachshund (DACH1), suppressed EMT via repression of cytoplasmic translational induction of Snail by inactivating the Y box–binding protein (YB-1). In the nucleus, DACH1 antagonized YB-1–mediated oncogenic transcriptional modules governing cell invasion. DACH1 blocked YB-1–induced mammary tumor growth and EMT in mice. In basal-like breast cancer, the reduced expression of DACH1 and increased YB-1 correlated with poor metastasis-free survival. The loss of DACH1 suppression of both cytoplasmic translational and nuclear transcriptional events governing EMT and tumor invasion may contribute to poor prognosis in basal-like forms of breast cancer, a relatively aggressive disease subtype. Cancer Res; 74(3); 829–39. ©2013 AACR.
Data from Neuroplastic Changes Occur Early in the Development of Pancreatic Ductal Adenocarcinoma
Authors: Stopczynski Rachelle E. , Normolle Daniel P. , Hartman Douglas J. , Ying Haoqiang , DeBerry Jennifer J. , Bielefeldt Klaus , Rhim Andrew D. , DePinho Ronald A. , Albers Kathryn M. , Davis Brian M.
Published: March 2023

Abstract
Perineural tumor invasion of intrapancreatic nerves, neurogenic inflammation, and tumor metastases along extrapancreatic nerves are key features of pancreatic malignancies. Animal studies show that chronic pancreatic inflammation produces hypertrophy and hypersensitivity of pancreatic afferents and that sensory fibers may themselves drive inflammation via neurogenic mechanisms. Although genetic mutations are required for cancer development, inflammation has been shown to be a precipitating event that can accelerate the transition of precancerous lesions to cancer. These observations led us to hypothesize that inflammation that accompanies early phases of pancreatic ductal adenocarcinoma (PDAC) would produce pathologic changes in pancreatic neurons and innervation. Using a lineage-labeled genetically engineered mouse model of PDAC, we found that pancreatic neurotrophic factor mRNA expression and sensory innervation increased dramatically when only pancreatic intraepithelial neoplasia were apparent. These changes correlated with pain-related decreases in exploratory behavior and increased expression of nociceptive genes in sensory ganglia. At later stages, cells of pancreatic origin could be found in the celiac and sensory ganglia along with metastases to the spinal cord. These results demonstrate that the nervous system participates in all stages of PDAC, including those that precede the appearance of cancer. Cancer Res; 74(6); 1718–27. ©2014 AACR.
Data from Genome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor Sensitivity
Authors: Bajrami Ilirjana , Frankum Jessica R. , Konde Asha , Miller Rowan E. , Rehman Farah L. , Brough Rachel , Campbell James , Sims David , Rafiq Rumana , Hooper Sean , Chen Lina , Kozarewa Iwanka , Assiotis Ioannis , Fenwick Kerry , Natrajan Rachael , Lord Christopher J. , Ashworth Alan
Published: March 2023

Abstract
Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest. Cancer Res; 74(1); 287–97. ©2013 AACR.
Data from Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition
Authors: Wang Yanping , Sparwasser Tim , Figlin Robert , Kim Hyung L.
Published: March 2023

Abstract
Inhibition of mTOR signaling enhances antitumor memory lymphocytes. However, pharmacologic mTOR inhibition also enhances regulatory T-cell (Treg) activity. To counter this effect, Treg control was added to mTOR inhibition in preclinical models. Tregs were controlled with CD4-depleting antibodies because CD4 depletion has high translational potential and already has a well-established safety profile in patients. The antitumor activity of the combination therapy was CD8 dependent and controlled growth of syngeneic tumors even when an adoptive immunotherapy was not used. Lymphocytes resulting from the combination therapy could be transferred into naïve mice to inhibit aggressive growth of lung metastases. The combination therapy enhanced CD8 memory formation as determined by memory markers and functional studies of immune recall. Removal of FoxP3-expressing T lymphocytes was the mechanism underlying immunologic memory formation following CD4 depletion. This was confirmed using transgenic DEREG (depletion of regulatory T cells) mice to specifically remove Foxp3+ T cells. It was further confirmed with reciprocal studies where stimulation of immunologic memory because of CD4 depletion was completely neutralized by adoptively transferring tumor-specific Foxp3+ T cells. Also contributing to tumor control, Tregs that eventually recovered following CD4 depletion were less immunosuppressive. These results provide a rationale for further study of mTOR inhibition and CD4 depletion in patients. Cancer Res; 74(8); 2217–28. ©2014 AACR.
Data from FANCJ Localization by Mismatch Repair Is Vital to Maintain Genomic Integrity after UV Irradiation
Authors: Guillemette Shawna , Branagan Amy , Peng Min , Dhruva Aashana , Schärer Orlando D. , Cantor Sharon B.
Published: March 2023

Abstract
Nucleotide excision repair (NER) is critical for the repair of DNA lesions induced by UV radiation, but its contribution in replicating cells is less clear. Here, we show that dual incision by NER endonucleases, including XPF and XPG, promotes the S-phase accumulation of the BRCA1 and Fanconi anemia–associated DNA helicase FANCJ to sites of UV-induced damage. FANCJ promotes replication protein A phosphorylation and the arrest of DNA synthesis following UV irradiation. Interaction defective mutants of FANCJ reveal that BRCA1 binding is not required for FANCJ localization, whereas interaction with the mismatch repair (MMR) protein MLH1 is essential. Correspondingly, we find that FANCJ, its direct interaction with MLH1, and the MMR protein MSH2 function in a common pathway in response to UV irradiation. FANCJ-deficient cells are not sensitive to killing by UV irradiation, yet we find that DNA mutations are significantly enhanced. Thus, we considered that FANCJ deficiency could be associated with skin cancer. Along these lines, in melanoma we found several somatic mutations in FANCJ, some of which were previously identified in hereditary breast cancer and Fanconi anemia. Given that, mutations in XPF can also lead to Fanconi anemia, we propose collaborations between Fanconi anemia, NER, and MMR are necessary to initiate checkpoint activation in replicating human cells to limit genomic instability. Cancer Res; 74(3); 932–44. ©2013 AACR.