Breast cancer etiology and pathogenesis remain unclear, but several observations suggest a role for the mitogen activated protein (MAP) kinase cascade in breast cancer progression.
The aim of our study is to understand the mechanism by which breast cancer cells grow and enhance invasion into surrounding tissues a characteristic feature of malignant tumors. It was previously shown that in breast cancer, most growth and oncogenic signals that leads to tyrosine phosphorylation activates MAPK cascade. The activated MAPK (ERK1 and ERK2) translocates from cytoplasm to the nucleus where it regulates nuclear proteins and transcriptional factors such as AP-1 which regulate proteases such as urokinase (uPA) and matrix metalloproteinase (MMP-9) that are shown to be involved in matrix degradation. Our preliminary studies using breast cancer cells suggest that down regulation of MAPK activity disrupt cell proliferation, motility and invasion phenotype, suggesting that activation of MAPK cascade, might be part of both normal cellular events and oncogenic transformation. This proposal is based on the hypothesis that overexpression and/or consistent activation of MAPK in breast epithelial cells results in increased protease induction and cell motility, leading to the acquisition of an invasive phenotype in breast and other tumor. We have three objectives: (1) To study the effect of MAPK (ERK1) overexpression and/or activation on cell transformation in breast epithelial cells. (2) To study the role of activated MAPK in the induction of tumorigenicity and metastasis. (3) To determine the importance of the MAPK in the induction of benign proliferative and malignant changes in mammary gland using transgenic mice. These studies will provide important new information on the mechanism of breast cancer development and progression. The long term goal is the identification of molecular events underlying tumor progression that are potential targets for the development of rational therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083964-02
Application #
6342192
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1999-12-16
Project End
2003-11-30
Budget Start
2000-12-02
Budget End
2001-12-01
Support Year
2
Fiscal Year
2001
Total Cost
$236,609
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Reddy, Kaladhar B; Glaros, Selina (2007) Inhibition of the MAP kinase activity suppresses estrogen-induced breast tumor growth both in vitro and in vivo. Int J Oncol 30:971-5
Glaros, Selina; Atanaskova, Natasha; Zhao, Changqing et al. (2006) Activation function-1 domain of estrogen receptor regulates the agonistic and antagonistic actions of tamoxifen. Mol Endocrinol 20:996-1008
Nabha, Sanaa M; Glaros, Selina; Hong, Meng et al. (2005) Upregulation of PKC-delta contributes to antiestrogen resistance in mammary tumor cells. Oncogene 24:3166-76
Kruger, Joseph S; Reddy, Kaladhar B (2003) Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells. Mol Cancer Res 1:801-9
Reddy, Kaladhar B; Nabha, Sanaa M; Atanaskova, Natasha (2003) Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev 22:395-403
Keshamouni, Venkateshwar G; Mattingly, Raymond R; Reddy, Kaladhar B (2002) Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta. J Biol Chem 277:22558-65
Atanaskova, Natasha; Keshamouni, Venkateshwar G; Krueger, Joseph S et al. (2002) MAP kinase/estrogen receptor cross-talk enhances estrogen-mediated signaling and tumor growth but does not confer tamoxifen resistance. Oncogene 21:4000-8
Reddy, K B; McGowen, R; Schuger, L et al. (2001) Maspin expression inversely correlates with breast tumor progression in MMTV/TGF-alpha transgenic mouse model. Oncogene 20:6538-43
Krueger, J S; Keshamouni, V G; Atanaskova, N et al. (2001) Temporal and quantitative regulation of mitogen-activated protein kinase (MAPK) modulates cell motility and invasion. Oncogene 20:4209-18