Abstract

Breast cancer is among the most common forms of cancer with over 180,000 new cases diagnosed In the USA each year. Approximately half of all breast cancer patients die from the disease because metastatic breast cancer remains a generally incurable and fatal disease. Cytotoxic drug treatment is an important weapon against cancer. However, cancerous cells frequently develop drug resistance to these agents. We have determined that activation of the Ras/Raf/MEWERK signal transduction cascade will lead to an increased ability of MCF-7 breast cancer cells to proliferate in the presence of the chemotherapeutic drugs doxorubicin and paclitaxel. Consequences of Raf activation may include increased expression of the drug transporter mdr-1, the anti-apoptoticbcl-2 gene, and autocrine growth factors such as such as amphiregulin which bind the HER2 growth factor receptor implicated in the etiology of breast cancer. In the proposed studies, we will determine whether induction of mdr-1, bcl-2and autocrine growth factor expression by theRas/Raf/MEWERK signal transduction pathway is essential for induction of breast cancer drugResistance and the mechanisms by which this occurs. To achieve these objectives, three specific aims have been proposed:
Aim 1. To determine mechanisms by which the Ras/Raf/MEWERK pathway regulates mdr-1, bcl-2, and autocrine growth factors and whether their induced expression is required for breast cancer drug resistance ,Aim 2. To determine mechanisms by which the Ras/Raf/MEWERK and Ras/PI3K/PTEN/PDK/Akt pathways interact and regulate mdr-1, bcl-2 and Breast cancer drug resistance.
Aim 3. To determine mechanisms by which Ras/Raf/MEWERK Pathway influences the redox status of breast cancer cells to modulate their sensitivity to Chemotherapeutic drugs. Through these studies, more information will be available to treat breast and other cancer patients with combinations of drugs, which inhibit signal transduction and anti-apoptotic pathways leading to drug resistance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098195-04
Application #
6993578
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Forry, Suzanne L
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
4
Fiscal Year
2006
Total Cost
$303,094
Indirect Cost

  Institution

Name
East Carolina University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858

  Publications

Taylor, Jackson R; Lehmann, Brian D; Chappell, William H et al. (2011) Cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. Oncotarget 2:610-26
Steelman, Linda S; Navolanic, Patrick; Chappell, William H et al. (2011) Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells. Cell Cycle 10:3003-15
Sokolosky, Melissa L; Stadelman, Kristin M; Chappell, William H et al. (2011) Involvement of Akt-1 and mTOR in sensitivity of breast cancer to targeted therapy. Oncotarget 2:538-50
McCubrey, James A; Abrams, Stephen L; Stadelman, Kristin et al. (2010) Targeting signal transduction pathways to eliminate chemotherapeutic drug resistance and cancer stem cells. Adv Enzyme Regul 50:285-307
Abrams, Stephen L; Steelman, Linda S; Shelton, John G et al. (2010) Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy. Cell Cycle 9:1839-46
Steelman, Linda S; Abrams, Stephen L; Shelton, John G et al. (2010) Dominant roles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs. Cell Cycle 9:1629-38
Abrams, Stephen L; Steelman, Linda S; Shelton, John G et al. (2010) The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 9:1781-91
Martelli, Alberto M; Evangelisti, Camilla; Chiarini, Francesca et al. (2010) The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget 1:89-103
Misaghian, N; Ligresti, G; Steelman, L S et al. (2009) Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia 23:25-42
Chiarini, Francesca; Fala, Federica; Tazzari, Pier Luigi et al. (2009) Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res 69:3520-8

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