There is compelling evidence derived from studies demonstrating inactivating mechanisms in human tumors and genetically modified mice indicating that the TGF-b signal transduction pathway is tumor suppressive. There is also compelling evidence that TGF-b can enhance the progression of mammary tumors. Carcinoma cells frequently lose the growth inhibitory response to TGF-b accompanied by an increased production of TGF-b. The locally high levels of TGF-b can then have effects on host cells (immunosuppressive and angiogenesis) or tumor cells (increased plasticity and motility) that would favor progression to a more malignant phenotype. Recent advances in the understanding of TGF-b signal transduction have provided some insights into how these diverse effects of TGF- b may occur. Current evidence indicates that the SMAD pathway is necessary for growth inhibition while the Rho proteins and the stress-activated kinase (JNK, p38) pathways are likely operative both in transcriptional regulation and cell shape changes. Based on this background, the applicant has formulated the following interrelated hypotheses: 1. Endogenous TGF-b's acting through the TGF-b receptors function to suppress both mammary epithelial proliferation and tumor formation. 2. Partial loss of type II TGF-b receptor (TbRII)) function in mammary epithelial cells will lead to loss of TGF-b growth inhibition and increased mammary tumor formation and synergize with oncogene activation to give highly aggressive tumors due in part to continued TGF-b autocrine stimulation of fibroblastoid morphology and increased mobility changes likely mediated through Rho proteins and stress activated kinase pathways. 3. Complete loss of TbRII in mammary epithelial cells will lead to increased mammary tumors but these tumors will be less aggressive due in part to absence of autocrine TGF-b action on tumor cells. The following specific aims are proposed to test these hypotheses: 1) Characterize spontaneous mammary tumor formation in mice expressing both MMTV-DNIIR (dominant negative type II receptor construct) and MMTV-TGF or MMTV-c-neu transgenes providing a model of partial loss of TbRII function. 2) Characterize the developmental phenotype of the mammary gland and mammary tumor formation in association with conditional knock-out of TbRII in mammary epithelial cells by cross breeding floxed TbRII mice (Tgfbr2floxE2) with MMTV-Cre mice. This will provide a model of complete loss of TbRII. 3) Determine the effect of decreased functional TbRII levels and different TGF-b signaling pathways on growth inhibition and conversion to a fibroblastoid morphology in NMUMG cells and cultures of carcinoma cells from aims 1 and 2.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA085492-05
Application #
6732140
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
2000-05-20
Project End
2005-11-30
Budget Start
2004-05-01
Budget End
2005-11-30
Support Year
5
Fiscal Year
2004
Total Cost
$406,223
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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