Cell, Molecular, and Tumor Biology最新文献

{"title":"Abstract B59: Race-related differential splicing of the insulin receptor: A novel target underlying prostate cancer disparities","authors":"April E. Deveaux, Bi-Dar Wang, B. LaCroix, Brendon M. Patierno, Dadong Zhang, K. Owzar, N. Lee, D. George, J. Freedman, S. Patierno","doi":"10.1158/1538-7755.DISP17-B59","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B59","url":null,"abstract":"Background: Age-adjusted incidence and mortality rates for prostate cancer (PCa) among African American (AA) men are significantly greater than among white men. Much of this disparity remains after controlling for behavioral, social, and neighborhood determinants of health, which is consistent with a biologic contribution. Evidence suggests that the genetic etiology and molecular progression of PCa are different in AAs versus whites. Our laboratory has identified novel alternatively spliced genes in AA versus white PCa biopsy tissue that track with population-based prostate tumor aggressiveness. This work addresses the urgent need to interrogate novel molecular mechanisms driving more aggressive PCa in AAs to aid in development of new biomarkers and therapeutic targets for improved prognosis and treatment of aggressive disease. Methods: We have analyzed RNA from human PCa biopsy tissue from 20 AA and 15 white patients using exon arrays. From these data, we prioritized targets for further study by identifying those associated with androgen signaling and PCa and those that have also been shown to be alternatively spliced in breast, lung, and liver cancer. To validate race-related alternative splicing of the insulin receptor (INSR) gene, we have used qPCR and targeted sequencing of RNA from population-specific PCa cell lines and patient-derived explants. In addition, we have knocked down the INSR splice variants in population-specific PCa cell lines using isoform-specific siRNAs and assessed resulting alterations in proliferation using a WST-1 proliferation assay. Current studies include assessing additional resulting alterations in expression of selected key targets in INSR signaling using Western blot analysis. In addition, studies are under way to treat population-specific PCa cell lines with INSR signaling inhibitors and assess resulting alterations in PCa cell biology. Results: Exon array analysis of RNA from AA and white PCa biopsy tissue revealed 934 differentially expressed exons in 861 corresponding genes. Thirty-nine targets have been prioritized for further study. We have validated race-related alternative splicing of INSR, involving differential exon inclusion/skipping of exon 11, in population-specific PCa cell lines and patient-derived explants, with the exclusion of exon 11 occurring more often in preclinical models of white PCa. Knockdown of INSR splice variants in population-specific PCa cell lines has shown that decreased expression of the isoform excluding exon 11 inhibits proliferation while decreased expression of the isoform including exon 11 has no effect on proliferation. Further studies to assess additional resulting alterations in expression of selected key targets in INSR signaling are under way. In addition, studies are under way to treat population-specific PCa cell lines with INSR signaling inhibitors and assess resulting alterations in PCa cell biology. Conclusions: These studies identify differential splicing of INSR ","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129496078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B63: Race and triple-negative breast cancer: Advances in noncoding RNA research together with a systems-biology-level analysis uncover key molecular differences","authors":"Aristeidis G. Telonis, I. Rigoutsos","doi":"10.1158/1538-7755.DISP17-B63","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B63","url":null,"abstract":"Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is characterized by marked differences between Black/African-American (B/Aa) and White (Wh) women. Despite the great progress that has been achieved towards understanding the causes of race disparities in TNBC, there have been no system-level investigations of the problem from the standpoint of molecular oncology. We used the transcriptomic data from The Cancer Genome Atlas (TCGA) repository to study the normal breast and TNBC samples from Wh and B/Aa TNBC individuals that are contained in it. Specifically, our analysis integrated transcriptomic data from messenger RNAs (mRNAs), microRNAs (miRNAs), miRNA isoforms (isomiRs), and tRNA-derived fragments (tRFs). IsomiRs and tRFs are constitutive regulatory molecules that target genes and pathways through RNA interference (RNAi). In addition to RNAi, isomiRs and tRFs also have other modes of action that are not yet understood. IsomiRs and tRFs represent recent and very important advances in our understanding of post-transcriptional regulation in the cell. What makes them particularly relevant for this study is our having shown that the “footprint” of isomiRs and tRFs that are active in a cell depends strongly on a person9s gender, race, and population origin, as well as on tissue type, tissue state, and disease type/subtype. We analyzed and compared TCGA samples from normal breast and TNBC and did so separately for B/Aa and Wh donors. As expected, we found many mRNAs to be differentially expressed. More importantly, when we compared B/Aa and Wh TNBC patients we found many mRNAs to be differentially wired. By this we mean that, even though the two groups of patients have many regulators and effectors in common, there are very extensive differences in the manner regulators interact with effectors in B/Aa and in Wh TNBC patients, respectively. Our accumulated evidence suggests strongly that this differential wiring is an important driver of the phenotypic differences that we observe between B/Aa and Wh TNBC patients. Our studies show that there is a multitude of regulatory molecules that are involved in this rewiring and the racial disparities in TNBC. Among isomiRs, we identified numerous isomiRs that arise from the mir-200c and mir-21 miRNA precursors, and from the oncogenic miR-17/92 and miR-183/96/182 clusters. Among tRFs, we identified many tRFs that arise from nuclear (e.g., Glycine, Leucine) and mitochondrial tRNAs (e.g., Valine, Proline). We showcase this race-specific rewiring with the help of MAPK and Wnt signaling, two metastasis-related pathways. The data-driven approaches that we employed in the analysis enabled us to carry out comprehensive studies of the transcriptomes of two states (normal and cancer) and two races (B/Aa and Wh). Our methodology allowed us to dissect the complex regulatory events that are mediated by isomiRs and tRFs. It also helped us unravel the significant roles that isomiRs and tRFs have in reshap","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"282 ","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"113983031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract C46: Fruit and vegetable intake and lung cancer incidence among Black women according to cigarette smoking status","authors":"S. Nomura, C. Dash, L. Rosenberg, J. Palmer, L. Adams-Campbell","doi":"10.1158/1538-7755.DISP17-C46","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-C46","url":null,"abstract":"Objective: The objective of this project was to evaluate associations of fruit and vegetable intake, according to cigarette smoking history, with lung cancer incidence among U.S. Black women. Methods: The Black Women9s Health Study is a prospective cohort study (analytic cohort=46,889) among Black women between the ages 21-69 at baseline (1995). Fruit and vegetable intake (collected in 1995 and 2001only) and smoking history were ascertained via questionnaires at baseline and during follow-up (every other year). Combined fruit and vegetable ( 1 servings/day), and cruciferous vegetable ( 1 servings/day) intakes were evaluated. Cigarette smoking measures that were evaluated include: 1) current smoking status (never, former, current 2 tests were utilized to assess interactions between smoking history and fruit and vegetable intake. Results: More than half the women reported no history of cigarette smoking (66.4%), while 18.4% were former smokers and 15.1% were current smokers ( Conclusion: Low fruit and vegetable intake was widespread in this population of U.S. Black women, but results do not support an association between fruit and vegetable intake and lung cancer incidence, regardless of cigarette smoking history. Citation Format: Sarah JO Nomura, Chiranjeev Dash, Lynn Rosenberg, Julie Palmer, Lucile L. Adams-Campbell. Fruit and vegetable intake and lung cancer incidence among Black women according to cigarette smoking status [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C46.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"97 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115664953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B56: Regulation of CXCR5-CXCL13 signaling in prostate cancer etiologic disparities","authors":"Adaugo Q. Ohandjo, C. Dill, C. Dongquan, J. Lillard","doi":"10.1158/1538-7755.DISP17-B56","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B56","url":null,"abstract":"The prevalence of prostate cancer (PCa) has been a worldwide burden. Cancer of the prostate is the most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the United States and Europe. There is a major health disparity associated with PCa; the number of fatalities associated with this disease is more significant in African-American (AA) men than in European American (EA) men. Disease progression occurs despite hormone ablation therapy, which leads to a condition called castration-resistant prostate cancer (CRPC). Further complicating the matter, CRPC is a disease that affects a variety of patients differently, which can be problematic for physicians to provide standardized treatments with similar outcomes. AAs with CRPC can experience significantly lower rates of overall survival, faster rates of tumor progression, and poor responses to chemotherapy compared to EAs with this disease. We previously showed that CXCL13:CXCR5 axis plays a role in PCa pathobiology and is also associated with PCa aggressiveness; CXCR5 signaling mediates PCa cell growth, migration, invasion, and docetaxel resistance. To further understand the implication of CXCR5-CXCL13 in CRPC, we characterize the reason behind the health disparities seen across groups of PCa patients by evaluating the difference in regulatory molecules (miRNAs) on CXCL13-CXCR5 signaling. We found the expression profile of CXCL13 and CXCR5 RNA to be associated with miRNAs (miR-140-3p.1, miR-24-3p, miR-200c, miR-221-3p/22-3p, miR-192-5p/215-5p, miR-214-5p). Using RNA-seq datasets from the Gene Expression Omnibus (GEO) and the Sequence Read Archive (SRA), CXCL13 and CXCR5 RNA as well as associated miRNAs (miR-140-3p.1, miR-24-3p, miR-221-3p/22-3p, miR-192-5p/215-5p, and miR-214-5p) were defined by etiologic disparities among PCa patients; this correlation is different among AA men compared to EA men. Understanding PCa and specifically CRPC disparities requires a better understanding of the race-specific differences in prostate tumor biology, molecules leading to prostate inflammation, and the mechanisms associated with CRPC therapeutic resistance and its aggressive phenotype. Citation Format: Adaugo Queen Ohandjo, Courtney Dill, Chen Dongquan, James W. Lillard, Jr.. Regulation of CXCR5-CXCL13 signaling in prostate cancer etiologic disparities [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B56.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"101 2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122974629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR04: Development of a novel therapeutic splice-switching oligonucleotide targeting race-related androgen receptor signaling and aggressive prostate cancer","authors":"B. LaCroix, Brendon M. Patierno, B. Sullenger, D. George, S. Patierno, J. Freedman","doi":"10.1158/1538-7755.disp17-pr04","DOIUrl":"https://doi.org/10.1158/1538-7755.disp17-pr04","url":null,"abstract":"","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"179 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123840641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B58: The role of epigenetic reader and alternative mRNA splicing variant MBD2_v2 in IL6 signaling in prostate cancer","authors":"E. Girsch, B. Bao, C. Mitrea, W. Sakr, G. Dyson, I. Powell, Aliccia Bollig-Fischer","doi":"10.1158/1538-7755.DISP17-B58","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B58","url":null,"abstract":"Background: African American men (AAM) have a 60% higher risk of being diagnosed with prostate cancer and a 2 to 3 times greater risk of dying from the disease compared to European American men (EAM). We previously reported evidence of molecular underpinnings for these disparities from high-throughput gene expression analysis of prostate cancer (PCa) specimens. The data showed that proinflammatory cytokine signaling factors, including IL6 and TGFB1, are significantly over-represented in PCa specimens from AAM. The limitation of that study, however, is that it did not investigate the potential molecular diversity for high-grade PCa, and it did not consider adjacent noncancer tissue. Methods: We conducted a pilot RNA-sequencing study of high-grade PCa, GS greater or equal to 7(4+3), and matched non-cancer adjacent prostate tissue specimens from AAM and EAM. We also studied the molecular biology of PCa cell lines derived from AAM and EAM tumors. Results: According to our genomic analysis, IL6 was once again relevant to our research, this time upregulated in PCa specimens from EAM, but also higher in the stromal compartment in AAM. Also, we noted that whether or not a PCa cell line expresses IL6 appears to be linked to TP53 mutation status. Moreover, cell lines derived from AAM (MDA-PCa-2b and RC77T), which are TP53 wild-type, did not express IL6 and showed an increased stem cell-like phenotype in response to IL6 treatment that was dose dependent. PCa cell lines that are TP53 mutant and expressed IL6 did not respond to exogenous IL6 treatment. We uncovered that in responsive PCa cell lines, IL6 treatment induced mRNA and protein expression of the epigenetic reader methyl CpG binding domain protein 2 (MBD2), more specifically the alternative mRNA splicing variant MBD2_v2. Further investigation validated that this short isoform promotes self-renewal and expansion of PCa stem cell-like cells. Conclusion: The outcomes suggest that there may be a dual nature for IL6 signaling in PCa that remains to be understood, yet contributes to the molecular diversity of high-grade prostate cancer and race disparities. Citation Format: Emily Girsch, Bin Bao, Cristina Mitrea, Wael A. Sakr, Gregory Dyson, Isaac Powell, Aliccia Bollig-Fischer. The role of epigenetic reader and alternative mRNA splicing variant MBD2_v2 in IL6 signaling in prostate cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B58.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"46 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126642220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B75: Nutritional profiling reveals glutamine-utilizing transaminases as a metabolic vulnerability of TAZ/YAP-driven breast cancer cells","authors":"Eleni Stampouloglou, N. Kingston, Chih-Sheng Yang, Liye Zhang, S. Monti, X. Varelas","doi":"10.1158/1538-7755.DISP17-B75","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B75","url":null,"abstract":"The aberrant activity of the transcriptional regulators TAZ and YAP (TAZ/YAP) drives many oncogenic traits, including the resistance to cell death, sustaining cell growth, and control of cell fate. Aggressive breast cancers in particular exhibit high TAZ/YAP levels and activity, and thus understanding the roles of these factors may offer therapeutic opportunity for these poorly treatable diseases. Here, we report that TAZ/YAP play an important role in driving breast cancer dependency to exogenous glutamine, an abundant amino acid that has emerged as central for tumor growth. We observed that breast cancer cells with high levels of TAZ/YAP are more sensitive to glutamine deprivation, and that knockout of TAZ/YAP in these cells alleviated defects resulting from glutamine. Rescue experiments with glutamine-derived metabolites suggested an essential role for glutamate and α-ketoglutarate (AKG) in TAZ/YAP-driven cell growth. Analysis of enzymes mediating the conversion of glutamate to α-ketoglutarate (AKG) showed that TAZ/YAP induce the expression of distinct transaminases, and that TAZ/YAP activity positively correlates with transaminase expression in breast cancer patients. Notably, the transaminase inhibitor aminooxyacetate (AOA) repressed cell growth in a TAZ/YAP-dependent manner, identifying transamination as a potential vulnerable metabolic requirement for TAZ/YAP-driven breast cancer. Considering the link between breast cancer risk and obesity, and the connection between obesity-driven metabolic changes to glutamine metabolism, our study offers a potential direction for future therapeutic targeting of aggressive breast cancers in underserved populations, where obesity is becoming a prevalent factor. Citation Format: Eleni Stampouloglou, Nathan Kingston, Chih-Sheng Yang, Liye Zhang, Stefano Monti, Xaralabos Varelas. Nutritional profiling reveals glutamine-utilizing transaminases as a metabolic vulnerability of TAZ/YAP-driven breast cancer cells [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B75.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124397941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B73: SOX2 regulation of FOXP1 as a mechanism driving disparate aggressiveness of prostate cancer in African-American men","authors":"Anthony Williams, Larischa de Wet, Marc Gillard, Steven Kregel, Tzintzuni I. Garcia, R. Szmulewitz, D. V. Griend","doi":"10.1158/1538-7755.DISP17-B73","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B73","url":null,"abstract":"Background: Although organ-confined, moderately graded prostate cancer has encouraging cure rates, progression to castration-resistant prostate cancer (CRPC) from advanced, high-grade lesions represents the lethal form of this malignancy, for which current therapeutic modalities are only palliative; patients with CRPC will die from their disease. Importantly, African-American (AA) men exhibit both a higher incidence of prostate cancer diagnoses and are at higher risk of developing CRPC as compared to other racial groups. Currently, the mechanisms driving prostate cancer disparities in AA men are poorly understood, and new biomarkers and novel drugs to address this disparity are in high demand to improve personalized medicine and clinical management of prostate cancer in AA men. Work by our group and others has identified SOX2 (sex determining region Y-box 2), an essential transcription factor for maintaining the survival and pluripotency of undifferentiated embryonic stem cells (ESCs), to be associated with aggressive prostate cancer and that the constitutive overexpression of SOX2 in a hormone-sensitive, SOX2-negative prostate cancer cell line is sufficient to generate a castration-resistant phenotype both in vitro and in vivo. Further, our data demonstrate canonical SOX2 transcriptional cofactors OCT4 and NANOG are frequently not expressed in prostate cancer, implying that SOX2 has unique, non-stem cell gene targets and binding partners within malignant prostate malignancies. Methods and Results: To elucidate such SOX2 gene targets in CRPC, we performed SOX2 chromatin immunoprecipitation and sequencing (ChIP-Seq) in prostate cancer cells, revealing SOX2 binding of several interesting and functionally important gene target promoters, including FOXP1, an AR target gene and transcription factor known to play a role in disparate aggressiveness of prostate cancer in African-American men. Based on these findings, we hypothesize that upon AR ablation in prostate cancer treatment, FOXP1, a tumor suppressor demonstrated to be associated with disparate prostate cancer aggressiveness in AA men, is repressed by SOX2 to drive CRPC in AA men. Work to test this hypothesis is currently under way, and includes (1) assessment of differential FOXP1 gene expression using MDA-PCa-2a, MDA-PCa-2b, and EA0066-hT, prostate cancer cell lines derived from AA men, and CWRR1, CWR22Rv1, and LNCaP, prostate cancer cell lines derived from CA men overexpressing SOX2 in the context of AR ablation; and (2) FOXP1 ChIP-Seq paired with RNA-Seq in tumor tissues prospectively collected from AA and CA men with prostate cancer undergoing radical prostatectomy. Conclusion: The work proposed herein represents an in-depth exploration of basic SOX2 biology in the context of CRPC, is highly innovative and translational, and has transformative potential to improve clinical patient management and eradicate disparities in CRPC. Note: This abstract was not presented at the conference. Citation ","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"51 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131515805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B68: EGFR signaling mediated modulation of transcription and probable crosstalk with components of Wnt signaling","authors":"M. Nava, Nwamaka A. Amobi, Nathan R Zemke, A. Berk, R. Farias-Eisner, J. Vadgama, Yanyuan Wu","doi":"10.1158/1538-7755.DISP17-B68","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B68","url":null,"abstract":"Introduction: The purpose of the study is to examine the crosstalk between HER2/EGFR and Wnt signaling in HER2-positive (HER2+) breast cancer cells. Human epidermal growth factor receptors (HER) constitute a family of four transmembrane receptors (HER1-HER4). Ligand binding to HER1 (EGFR), HER3, and HER4 results in heterodimerization with other HER family members, including HER2. HER2+ breast cancer is characterized by an amplification of the HER2 gene, resulting in an increase in HER2 protein presence on the surface of cells, magnification of downstream intracellular signaling, and enhanced responsiveness to ligand stimulation (e.g., EGF). Approximately 20-30% of breast cancers have HER2 amplifications. The Wnt pathway is highly conserved in mammals and overexpression of some Wnt family members results in cancer. Wnts are ligands that bind to Frizzled/LRP receptors to initiate downstream signaling that results in the stabilization and nuclear translocation of β-catenin. Once in the nucleus, β-catenin associates with activators such as TCF/LEF, SMADs, ATF2, and KLF4 to promote the transcription of many target genes. EGFR and Wnt crosstalk has been observed in various cell types following EGF treatment. As an example, EGF treatment of human epidermoid carcinoma cells results in β-catenin nuclear translocation and activation of TCF/LEF dependent reporters. Mitogen-Activated Protein Kinases (MAPKs), which are activated following EGF stimulation, have been demonstrated to inhibit GSK3β, a negative regulator of β-catenin. However, no genome-wide analysis has been conducted to determine what genes are regulated by β-catenin following EGF treatment in HER2+ breast cancer cells. We sought to determine the modulation of gene expression following the stimulation of HER2+ breast cancer cells with EGF and to investigate the mechanisms that underlie the changes observed in gene expression. Our studies have revealed exciting and novel findings that elucidate the effects of EGFR signaling on the epigenetic landscape. Specifically, we have identified putative β-catenin targets that become activated following EGFR stimulation. We hypothesize that EGFR signaling promotes the activation of specific β-catenin genes in order to alter cellular identity. Methods: RNA-seq and ChIP-seq for H3K18ac and H3K27ac was conducted following an EGF treatment time course in SKBR3 cells. The levels of several proteins of interest were determined by Western blot analysis. The cellular localization of proteins of interest was examined using biochemically fractionated lysates followed by Western blot analysis. Results: RNA-seq analysis following an EGF treatment time course revealed that approximately 2,200 genes are either upregulated or downregulated compared to untreated cells. Moreover, the expression profiles clearly demonstrated waves of transcription. Next, we determined the status of H3K18ac and H3K27ac using ChIP-seq following an EGF time course. We found that H3K18ac and H3K","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123131160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B72: DNA methylation and genetic alterations contribute to aggressive prostate cancer in African American men","authors":"S. Ramakrishnan, Xuan Peng, Qianya Qi, Q. Hu, G. Azabdaftari, E. Pop, J. Mohler, K. Attwood, Li Yan, Jianmin Wang, A. Woloszynska-Read","doi":"10.1158/1538-7755.DISP17-B72","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B72","url":null,"abstract":"Background: African-American (AA) men are more often diagnosed with early-onset aggressive prostate cancer than European American (EA) men. Prostate cancer health disparities between AA and EA men are attributed to socioeconomic as well as biologic differences existing between the two groups. The purpose of this study is to investigate how genetic and epigenetic alterations, specifically DNA methylation, contribute to early-onset aggressive prostate cancer in AA men. Methods: We performed 450K methylation array and RNA-sequencing on radical prostatectomy specimens from AA (n=32) and EA (n=5) men treated at Roswell Park Cancer Institute (RPCI). To increase analytical power, we included AA (n=22) and EA (n=172) patients from The Cancer Genome Atlas (TCGA) database. We found no significant difference in the average age between EA and AA men in the RPCI cohort, but the TCGA cohort consisted of AA men who had significantly lower average and median age compared to EA men (57 and 56 vs 61 and 62; p=0.019). We assessed baseline androgen receptor (AR) protein levels in matched benign and malignant AA (n=95) and EA (n=93) radical prostatectomy tissues from RPCI using immunohistochemistry. Gleason score 4+3 were classified as low and high aggressive tumors, respectively. Results: Unsupervised hierarchical clustering of DNA methylation levels in prostate cancers revealed 9 clusters. We focused on the 2 largest clusters, Cluster 1 (n=133) and Cluster 3 (n=73). Cluster 1 consisted predominantly of low aggressive disease (p=0.00002) with lower serum prostate specific antigen (PSA) values (8.97 vs 13.35 ng/ml) compared to Cluster 3. Following this trend, AA patients, but not EA patients, in Cluster 1 had better overall (57 vs 50 months, p=0.48) and disease-free time (47 vs 22 months, p=0.01) as compared to Cluster 3. ERG (ETS-related gene) fusion-positive prostate cancer is believed to be more aggressive than fusion-negative prostate cancer due to increased ERG gene transcription. We did not observe a difference in fusion status between the two DNA methylation clusters. However, overall DNA methylation was higher in fusion-negative samples as compared to fusion-positive samples in the TCGA dataset. ERG is known to bind to and reduce PSA, a direct downstream AR target. In the TCGA dataset, AA fusion-negative patients had higher average and median preoperative PSA values (18.38, 20.15 ng/ml) as compared with AA fusion-positive (7.51, 6.70 ng/ml), EA fusion-positive (9.43, 7.00 ng/ml), and EA fusion-negative patients (11.47, 7.50 ng/ml). There was no significant difference in the AR transcript and AR protein levels between fusion-positive and -negative AA and EA men. AR protein expression in RPCI cohort tissue microarrays showed that adjacent nontumor tissues from AA men had higher percent AR positive nuclei (p Conclusions: Analysis of the RPCI and TCGA cohorts indicated that DNA methylation separated low and high aggressive prostate cancer in AA men. Further analy","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"221 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114431388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}