Breast cancer affects one in every eight American women. One important research goal is determining how hormones act to accelerate or retard progression of disease. Programmed cell death or apoptosis is one mechanism which suppresses the development of cancer and tumor growth. The current work in our laboratory is focused on how development of resistance to p53-independent apoptosis accelerates breast cancer. We use a transgenic mouse model of mammary gland cancer which can be used to study the temporal progression of oncogenesis. In this model, oncogenesis is stimulated by expression of the oncogene, the SV40 T-antigen (Tag). We have demonstrated that expression of Tag stimulates p53-independent apoptosis at early timepoints. Resistance to p53-independent apoptosis develops after several months. In a related study, we showed that normal mammary gland involution is mediated by p53-independent apoptosis and that the apoptosis pathway genes, bax and bcl-x, mediate apoptosis in the mammary gland. We have established an in vitro whole mammary gland culture system which does not require priming by estrogen and progesterone. We would now like to use our experience to develop an in vitro whole gland culture system to study the induction of apoptosis. We will use this system to study how hormones and anti-hormones affect the induction of apoptosis in normal mammary gland, mammary gland tissue from Tag transgenic mice at different stages in the development of malignancy and in tumor tissue.
As specific aims, we propose to: 1) Establish an in vitro whole organ culture system to study the induction of apoptosis in normal and Tag transgenic mammary tissue and in tumor tissue. 2) Establish that the genetic apoptosis pathways utilized during the induction of apoptosis in vitro are the same pathways used in vivo. 3) Using the in vitro culture system, determine how treatment with hormones or anti-hormones affects the induction of apoptosis. 4) Using the in vitro culture system, determine how hormones or anti-hormones affect the expression of specific apoptosis pathway genes.
| Li, M; Lewis, B; Capuco, A V et al. (2000) WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis. Oncogene 19:1010-9 |
| Furth, P A (1997) Conditional control of gene expression in the mammary gland. J Mammary Gland Biol Neoplasia 2:373-83 |
| Li, M; Liu, X; Robinson, G et al. (1997) Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A 94:3425-30 |
