Consistent malignant transformation of human breast epithelial cells, or other human cells, in vitro by chemical or physical carcinogens has not been accomplished to date. Among the possible reasons for the failure are 1) the use of inappropriate target cells for transformation studies, i.e. differentiating cells instead of stem cells; and 2) the use of inappropriate laboratory animals as hosts for transformed cells. The major objective of this grant proposal is to examine the validity of these two possibilities. Recently we have observed the existence of a mall subpopulation of human kidney epithelial cells, with stem cell characteristics, i.e., extended life span and capable of contact- insensitive growth on a x-ray lethally irradiated human fibroblast cell mat. This, and our preliminary results, indicate that it is possible to enrich for human breast renewal capacity using the cell mat or an appropriate cell culture medium. Therefore we propose to transform these cells with chemical and physical carcinogens and to select neoplastic transformed cells by using 1) our x-ray lethally irradiated human fibroblast cell mat which, additionally, has been shown to allow the growth of human carcinomas of various origin but not normal cells (except the contact-insensitive putative transformed cells will be characterized biologically and biochemically to demonstrate that they are truly neoplastic transformed. The second major goal of this proposal is to develop new in vivo models capable of accepting and maintaining transformed mammary epithelial cells. The transplantation success rate and growth rate of primary mammary carcinoma (rat and human) and putative in vitro transformed human breast epithelial cells will be examined in 3 strains of immune deficient mice, i.e., conventional athymic nude mice (T-lymphocyte deficient), beige-XID athymic nude mice (T-lymphocyte deficient and LAK lymphocytes). The endocrine system of the immune deficient mice will be altered to provide a hormonal milieu that is rich in human mammotrophic hormones. In this research proposal, we feel that we are addressing and examining two very crucial components of the complex process of ex vivo neoplastic transformation of human breast epithelium, components that have not in the past received sufficient experimental attention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050430-03
Application #
3194889
Study Section
Special Emphasis Panel (SRC (50))
Project Start
1989-05-01
Project End
1993-02-28
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Michigan State University
Department
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Kao, C Y; Oakley, C S; Welsch, C W et al. (1997) Growth requirements and neoplastic transformation of two types of normal human breast epithelial cells derived from reduction mammoplasty. In Vitro Cell Dev Biol Anim 33:282-8
Zhai, Y F; Wirth, J J; Welsch, C W et al. (1996) Protein tyrosine phosphatases: cellular regulators of human breast cancer? Cancer Treat Res 83:107-25
Jou, Y S; Layhe, B; Matesic, D F et al. (1995) Inhibition of gap junctional intercellular communication and malignant transformation of rat liver epithelial cells by neu oncogene. Carcinogenesis 16:311-7
Kao, C Y; Nomata, K; Oakley, C S et al. (1995) Two types of normal human breast epithelial cells derived from reduction mammoplasty: phenotypic characterization and response to SV40 transfection. Carcinogenesis 16:531-8
Trosko, J E (1995) Biomarkers for low-level exposure causing epigenetic responses in stem cells. Stem Cells 13 Suppl 1:231-9
Zhai, Y; Wirth, J; Kang, S et al. (1995) LAR-PTPase cDNA transfection suppression of tumor growth of neu oncogene-transformed human breast carcinoma cells. Mol Carcinog 14:103-10
Zhai, Y F; Beittenmiller, H; Wang, B et al. (1993) Increased expression of specific protein tyrosine phosphatases in human breast epithelial cells neoplastically transformed by the neu oncogene. Cancer Res 53:2272-8
Oakley, C S; Welsch, M A; Zhai, Y F et al. (1993) Comparative abilities of athymic nude mice and severe combined immune deficient (SCID) mice to accept transplants of induced rat mammary carcinomas: enhanced transplantation efficiency of those rat mammary carcinomas that have elevated expression of neu o Int J Cancer 53:1002-7
Welsch, C W; Oakley, C S; Chang, C C et al. (1993) Suppression of growth by dietary fish oil of human breast carcinomas maintained in three different strains of immune-deficient mice. Nutr Cancer 20:119-27
Jou, Y S; Matesic, D; Dupont, E et al. (1993) Restoration of gap-junctional intercellular communication in a communication-deficient rat liver cell mutant by transfection with connexin 43 cDNA. Mol Carcinog 8:234-44

Showing the most recent 10 out of 11 publications