MEK5-Erk5 in breast cancer resistance

MEK5-Erk5 在乳腺癌抵抗中的作用

• 批准号: 8660659
• 负责人: Matthew E. Burow
• 金额: $ 29.2万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660659
• 关键词: AKT3 gene; Adjuvant; Aggressive behavior; Aromatase Inhibitors; Biological; Breast Cancer Cell; Breast Carcinoma; CREB1 gene; Cell Survival; Cell model; Data; Drug resistance; Endocrine; Estrogen Antagonists; Estrogens; Exhibits; Gene Expression; Gene Expression Profiling; Genes; Goals; Hormones; In Vitro; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Microarray Analysis; Mitogen-Activated Protein Kinases; Molecular; Molecular Target; Morphology; Neoplasm Metastasis; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Phosphotransferases; Play; Process; Prognostic Marker; Proto-Oncogene Proteins c-akt; Publishing; Regulation; Research; Resistance; Resistance development; Role; Signal Pathway; Signal Transduction; System; Tamoxifen; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transcription Factor AP-1; Transcriptional Regulation; Up-Regulation; Xenograft procedure; base; cancer cell; design; drug development; effective therapy; epithelial to mesenchymal transition; gene function; hormone therapy; in vivo; insight; malignant breast neoplasm; malignant phenotype; molecular marker; mouse model; novel; prospective; resistance mechanism; response; slug; small hairpin RNA; therapeutic development; tool; transcription factor; tumor; tumor progression; tumorigenesis

SUMMARY The development of resistance to therapeutic agents represents a significant obstacle in the effective treatment of cancer. At the molecular level this drug-resistance is characterized by changes in signaling and gene expression that promote survival and proliferation, ultimately allowing progression to a more malignant phenotype. The long-term objective of this research is to understand the role of the MEK5-Erk5 signaling pathway in the tumorigenesis and resistance of breast carcinoma with the goal of developing targeting strategies for therapeutic intervention. Using gene expression profiling and examination of cell signaling we have identified and implicated the MEK5-Erk5 pathway as a critical component of acquired resistance coordinate to acquisition of an EMT and ER¿-negative phenotype in breast cancer cells. Our preliminary data further suggests that MEK5-signaling functions through downstream transcription factors to mediate expression of EMT regulators (SLUG, ZEB1, ZEB2) and AKT3. Based upon this information we hypothesize that upregulation of MEK5-Erk5 signaling pathway induces the epithelial-to-mesenchymal transition, loss of ER¿ expression, and drives progression of breast cancer cells to a hormone-independent and therapeutically resistant phenotype. The proposed Specific Aims are designed to establish a role for MEK5 defining the specific mechanisms by which progression to a resistant phenotype occurs in vitro and in vivo. Aim#1: To test the hypothesis that Erk5 signaling is required for MEK5 -mediated breast cancer tumorigenesis and therapeutic resistance. Aim#2: To test the hypothesis that MEK5-Erk5 signaling functions in the progression to endocrine-independence and resistance through disruption of the ER¿-signaling axis. Aim#3: To test the hypothesis that the MEK5-Erk5 signaling axis promotes an epithelial-to-mesenchymal transition, ER¿-negative and invasive phenotype. In this proposal we expect to define and link a direct role the MEK5-Erk5 signaling pathway plays in the development of therapeutic resistance, and promotion of an aggressive phenotype in cancer cells. The establishment of this connection would define the MEK5-Erk5 pathway as potential molecular markers to be utilized as a prognostic indicator of therapeutic response and as a prospective molecular target for pharmacological drug development.

总结

项目成果

Sphingosine kinase isoforms as a therapeutic target in endocrine therapy resistant luminal and basal-A breast cancer.

• DOI: 10.1258/ebm.2012.012028
• 发表时间: 2012-07
• 期刊: Experimental biology and medicine (Maywood, N.J.)
• 作者: Antoon JW;White MD;Driver JL;Burow ME;Beckman BS
• 通讯作者: Beckman BS

Proteomic analysis of acquired tamoxifen resistance in MCF-7 cells reveals expression signatures associated with enhanced migration.

• DOI: 10.1186/bcr3144
• 发表时间: 2012-03-14
• 期刊: Breast cancer research : BCR
• 作者: Zhou C;Zhong Q;Rhodes LV;Townley I;Bratton MR;Zhang Q;Martin EC;Elliott S;Collins-Burow BM;Burow ME;Wang G
• 通讯作者: Wang G

Constitutive activation of MEK5 promotes a mesenchymal and migratory cell phenotype in triple negative breast cancer.

• DOI: 10.18632/oncoscience.535
• 发表时间: 2021
• 期刊: Oncoscience
• 作者: Matossian MD;Hoang VT;Burks HE;La J;Elliott S;Brock C;Rusch DB;Buechlein A;Nephew KP;Bhatt A;Cavanaugh JE;Flaherty PT;Collins-Burow BM;Burow ME
• 通讯作者: Burow ME

Discovery of a Series of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion.

• DOI: 10.1021/ml300322n
• 发表时间: 2013-02-14
• 期刊: ACS MEDICINAL CHEMISTRY LETTERS
• 影响因子: 4.2
• 作者: Zheng, Shilong;Zhong, Qiu;Jiang, Quan;Mottamal, Madhusoodanan;Zhang, Qiang;Zhu, Naijue;Burow, Matthew E.;Worthylake, Rebecca A.;Wang, Guangdi
• 通讯作者: Wang, Guangdi

Oncogenic signaling of MEK5-ERK5.

• DOI: 10.1016/j.canlet.2017.01.034
• 发表时间: 2017-04-28
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: Hoang VT;Yan TJ;Cavanaugh JE;Flaherty PT;Beckman BS;Burow ME
• 通讯作者: Burow ME