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.
While endocrine therapies; such as the anti-estrogen tamoxifen and the aromatase inhibitors; are importanttools in the treatment of ER(+) breast carcinoma in the adjuvant and metastatic setting some tumors ultimatelyprogresses to hormone-independence and resistance. Here we examine the role and mechanisms of the novelMEK5-Erk5 mitogen-activated protein kinase pathway in the regulation of cell survival and therapeuticresistance of breast cancer cells. We further examine the role of MEK5-Erk5 signaling in the progression ofbreast cancer cells to an ER?-negative and epithelial-to-mesenchymal transition phenotype. The research inthis proposal is about understanding mechanisms of resistance and developing strategies to target and treatbreast cancer progression.
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|Antoon, James W; White, Martin D; Slaughter, Evelyn M et al. (2011) Targeting NF?B mediated breast cancer chemoresistance through selective inhibition of sphingosine kinase-2. Cancer Biol Ther 11:678-89|
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