The broad objective of this project is to identify specific alterations in growth control mechanisms that are causally related to the neoplastic growth potential of rat mammary carcinoma (RMT) cells. To accomplish this, experiments have focused on understanding growth control mechanisms operative for normal rat mammary epithelial (RME) cells and from that perspective examining for normal rat mammary epithelial (RME) cells and from that perspective examining growth control in corresponding tumor derived cells. We have found that, whereas RME cells have a finite and reproducible proliferative lifespan in culture, every primary tumor examined has cells that are immortal with respect to their proliferative potential in culture. Despite this difference, no all immortal RMT cells express neoplastic potential when transplanted into syngeneic hosts. However, immortal RMT cells that also have become independent of growth factors strictly required by RME cells for growth in serum-free culture express high neoplastic potential upon transplantation to syngeneic recipients. Therefore, this project is aimed at determining the cellular and molecular basis for the acquisition of growth factor independence by neoplastic cells and to test directly the hypothesis that growth factor independence is causally related to neoplastic potential.
The specific aims are: 1) To determine if the loss of specific growth factor requirements by growth factor independent RMT cells results from growth factor synthesis by these cells and if so, to identify and characterize the autocrine factors responsible for this altered phenotype. 2) To determine if induction of growth factor independence in normal RME cells or in immortalized growth factor dependent RMT cells by chemical carcinogen treatment in vitro results in concomitant acquisition of neoplastic potential in vivo; and 3) To test the hypothesis that some (or all) growth factor independent RMT cells became so by mechanism not directly involving growth factor synthesis, but via activation of proto- oncogenes that are homologous to growth factor receptors, (e.g. c- erbB or e.g. c-erbB-2) or that act in growth factor mediated signal transduction (e.g. c-ras).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040064-06
Application #
3179519
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1985-07-01
Project End
1994-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ethier, S P; Kokeny, K E; Ridings, J W et al. (1996) erbB family receptor expression and growth regulation in a newly isolated human breast cancer cell line. Cancer Res 56:899-907
Ethier, S P; Langton, B C; Dilts, C A (1996) Growth factor-independent proliferation of rat mammary carcinoma cells by autocrine secretion of neu-differentiation factor/heregulin and transforming growth factor-alpha. Mol Carcinog 15:134-43
Ram, T G; Ethier, S P (1996) Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and erbB-3 is potently induced by neu differentiation factor/heregulin during mitogenesis and is constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 gene amplifi Cell Growth Differ 7:551-61
Ethier, S P; Mahacek, M L; Gullick, W J et al. (1993) Differential isolation of normal luminal mammary epithelial cells and breast cancer cells from primary and metastatic sites using selective media. Cancer Res 53:627-35
Mahacek, M L; Beer, D G; Frank, T S et al. (1993) Finite proliferative lifespan in vitro of a human breast cancer cell strain isolated from a metastatic lymph node. Breast Cancer Res Treat 28:267-76
Ethier, S P; Moorthy, R; Dilts, C A (1991) Secretion of an epidermal growth factor-like growth factor by epidermal growth factor-independent rat mammary carcinoma cells. Cell Growth Differ 2:593-602
Ethier, S P; Moorthy, R (1991) Multiple growth factor independence in rat mammary carcinoma cells. Breast Cancer Res Treat 18:73-81
Lowney, P; Corral, J; Detmer, K et al. (1991) A human Hox 1 homeobox gene exhibits myeloid-specific expression of alternative transcripts in human hematopoietic cells. Nucleic Acids Res 19:3443-9
Ethier, S P; Van de Velde, R M (1990) Secretion of a TGF-beta-like growth inhibitor by normal rat mammary epithelial cells in vitro. J Cell Physiol 142:15-20
Ethier, S P; Chiodino, C; Jones, R F (1990) Role of growth factor synthesis in the acquisition of insulin/insulin-like growth factor I independence in rat mammary carcinoma cells. Cancer Res 50:5351-7

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