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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125806-05
Application #
8660659
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$291,987
Indirect Cost
$85,046
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Burks, Hope E; Phamduy, Theresa B; Azimi, Mohammad S et al. (2016) Laser Direct-Write Onto Live Tissues: A Novel Model for Studying Cancer Cell Migration. J Cell Physiol 231:2333-8
Strong, Amy L; Ohlstein, Jason F; Biagas, Brandi A et al. (2015) Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers. Breast Cancer Res 17:112
Zhuang, Yan; Nguyen, Hong T; Burow, Matthew E et al. (2015) Elevated expression of long intergenic non-coding RNA HOTAIR in a basal-like variant of MCF-7 breast cancer cells. Mol Carcinog 54:1656-67
Phamduy, Theresa B; Sweat, Richard S; Azimi, Mohammad S et al. (2015) Printing cancer cells into intact microvascular networks: a model for investigating cancer cell dynamics during angiogenesis. Integr Biol (Camb) 7:1068-78
Bratton, Melyssa R; Martin, Elizabeth C; Elliott, Steven et al. (2015) Glyceollin, a novel regulator of mTOR/p70S6 in estrogen receptor positive breast cancer. J Steroid Biochem Mol Biol 150:17-23
Miller, David F B; Yan, Pearlly X; Fang, Fang et al. (2015) Stranded Whole Transcriptome RNA-Seq for All RNA Types. Curr Protoc Hum Genet 84:11.14.1-23
Rhodes, Lyndsay V; Martin, Elizabeth C; Segar, H Chris et al. (2015) Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer. Oncotarget 6:16638-52
Martin, Elizabeth C; Krebs, Adrienne E; Burks, Hope E et al. (2014) miR-155 induced transcriptome changes in the MCF-7 breast cancer cell line leads to enhanced mitogen activated protein kinase signaling. Genes Cancer 5:353-64
Martin, Elizabeth C; Rhodes, Lyndsay V; Elliott, Steven et al. (2014) microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity. Mol Cancer 13:229
Rhodes, Lyndsay V; Tate, Chandra R; Segar, H Chris et al. (2014) Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators. Breast Cancer Res Treat 145:593-604

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