Wwox and Fhit loss and the DNA damage response in breast cancer subtypes

Wwox 和 Fhit 丢失以及乳腺癌亚型中的 DNA 损伤反应

• 批准号: 8521109
• 负责人: KAY HUEBNER
• 金额: $ 15.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-18 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521109
• 关键词: African; Agreement; BRCA1 gene; Binding; Breast; Breast Cancer Cell; Cancer cell line; Carboplatin; Cell Line; Cell Nucleus; Cells; Chromosome Fragile Sites; Cisplatin; Clinical; Complex; Cytoplasm; Cytotoxic agent; DNA Damage; DNA Repair; DNA Repair Pathway; DNA damage checkpoint; Data; Defect; Development; Disseminated Malignant Neoplasm; ERBB2 gene; Epidermal Growth Factor Receptor; ErbB4 gene; FHIT gene; Funding; Genes; Genome; Gland; Goals; In Vitro; Infection; Knock-out; Knockout Mice; Laboratories; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mass Spectrum Analysis; Membrane; Modeling; Molecular; Multivariate Analysis; Mus; Neoplasms; Nickel; Nuclear; Nude Mice; Paclitaxel; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Predisposition; Proteins; Resistance; Risk; Role; Signal Pathway; Tamoxifen; Testing; Tissues; Transcription Factor AP-2 Alpha; Treatment outcome; Universities; Woman; Xenograft procedure; base; cancer therapy; chemotherapy; cytotoxic; cytotoxicity; high risk; in vivo; inhibitor/antagonist; killings; malignant breast neoplasm; mutant; neoplastic; promoter; research study; response; tissue culture; tumor; young woman

PROJECT SUMMARY / ABSTRACT In the last two years we have shown that: 1) Wwox, Ap2¿, and ErbB4 are independent markers of tamoxifen resistance. Reduced Wwox expression was better than PR in prediction of resistance, especially in high-risk patients, and nuclear Ap2¿ expression was better than Her2, especially in low-risk patients; 2) ErbB4 loss was an independent marker of tamoxifen resistance when adjusted for other significant predictors; 3) in vitro studies of tamoxifen resistant cells confirmed that Ap2¿ was bound by Wwox in the cytoplasm, released into the nucleus in Wwox negative, tamoxifen resistant cells and was a nuclear activator of HER2; 4) >800 invasive breast cancers on Tissue Micro Arrays (TMAs) were classified into specific subtypes: triple negative tumors (TN: ER, PR, HER2 negative, basal-like tumors) showed frequent expression of EGFR, CK5/6 and AP2¿ and frequent loss of Fhit and Wwox, suggesting that reduced Fhit and Wwox expression have roles in pathogenesis of basal differentiation in breast cancer. Alteration of expression of Fhit and Wwox occured in ~90% of the basal-like/TN breast cancers and may contribute to defects in DNA repair, as observed in BRCA1- deficient cancers. DNA damage response (DDR) proteins (¿H2AX, pChk2, p53) were expressed highly significantly more in TN and basal-like tumors. Thus, DDR checkpoint proteins could be targets for treatment of these cancers. Specific subtype breast cancer cell lines, for mechanistic studies, and TMAs with cores from primary and metastatic cancers with linked treatment and outcome data, for in vivo studies, will be used in experiments outlined in the following Aims: 1. Wwox effectors in breast cancer in vitro: a) using breast cancer cells of luminal A, HER2+ and TN/Basal subtypes, identify Wwox interactor proteins in specific subtypes, after infection with AdenoWWOX, isolation of the Wwox complex, followed by mass spectrometry identification of proteins in the complex; b) examine expression of candidate interactors in specific breast cancer subtypes in cell lines and tissues; 2. DNA damage response checkpoint inhibitors in breast cancer in vitro: a) Chk1 and Parp1 inhibitors will be tested for effect on specific breast cancer subtypes in tissue culture; b) Chk1 and Parp1 inhibitors, in combination with cytotoxic chemotherapeutic drugs, will be tested for effect on cytotoxicity of specific breast cancer subtypes; 3. Association of activated DDR checkpoint in breast cancers with treatment outcome: divide tumors on TMAs into subtypes based on ER, PR, HER2, EGFR, CK5,6 status; assess status of the DDR checkpoint proteins in tumors of each subtype and correlate markers with treatment and outcome; 4. Conditional mouse Wwox knockdown X Fhit knockout. The mouse cross will be examined for susceptibility to mammary gland cancer and mechanisms involved in development of normal and neoplastic glands. 1

项目摘要/摘要

项目成果

Fhit loss-associated initiation and progression of neoplasia in vitro.

• DOI: 10.1111/cas.13032
• 发表时间: 2016-11
• 期刊: Cancer science
• 影响因子: 5.7
• 作者: Karras JR;Schrock MS;Batar B;Zhang J;La Perle K;Druck T;Huebner K
• 通讯作者: Huebner K

FHIT loss-induced DNA damage creates optimal APOBEC substrates: Insights into APOBEC-mediated mutagenesis.

• DOI: 10.18632/oncotarget.2636
• 发表时间: 2015-02-20
• 期刊: Oncotarget
• 作者: Waters CE;Saldivar JC;Amin ZA;Schrock MS;Huebner K
• 通讯作者: Huebner K

WWOX: a fragile tumor suppressor.

• DOI: 10.1177/1535370214561590
• 发表时间: 2015-03
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Schrock MS;Huebner K
• 通讯作者: Huebner K

Fragile histidine triad protein, WW domain-containing oxidoreductase protein Wwox, and activator protein 2gamma expression levels correlate with basal phenotype in breast cancer.

• DOI: 10.1002/cncr.24103
• 发表时间: 2009-02-15
• 期刊: CANCER
• 影响因子: 6.2
• 作者: Guler, Gulnur;Huebner, Kay;Himmetoglu, Cigdem;Jimenez, Rafael E.;Costinean, Stefan;Volinia, Stefano;Pilarski, Robert T.;Hayran, Mutlu;Shapiro, Charles L.
• 通讯作者: Shapiro, Charles L.

Fhit down-regulation is an early event in pancreatic carcinogenesis.

下调是胰腺癌发生的早期事件。

• DOI: 10.1007/s00428-017-2105-3
• 发表时间: 2017-06
• 期刊: Virchows Archiv : an international journal of pathology
• 作者: Fassan M;Rusev B;Corbo V;Gasparini P;Luchini C;Vicentini C;Mafficini A;Paiella S;Salvia R;Cataldo I;Scarpa A;Huebner K
• 通讯作者: Huebner K