BCL2 GENE FAMILY, APOPTOSIS RESISTANCE AND BREAST CANCE

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DESCRIPTION: (adapted from the investigator's abstract) Long term objectives and health relatedness: Their research is focused on understanding how development of resistance to p53-independent apoptosis contributes to progression of breast cancer. Activation of programmed cell death or apoptosis within a developing cancer retards tumor progression. Some anti-cancer treatments reduce tumor size by inducing apoptosis. The aim of this proposal is to determine if simple overexpression of bcl-2 family member 'survival inducers' as compared to 'death inducers' is a mechanism of resistance to p53-independent apoptosis in breast undergoing malignant transformation. Bcl-2 family member survival and death inducers mediate apoptosis through the formation of homo- and hetero-dimers. This leads to the hypothesis that cell fate is determined directly by the relative abundance of survival and death inducers. Research Design: A transgenic mouse model of breast cancer in which induction of p53-independent apoptosis (WAP-Tag) will be used in conjunction with established transgenic lines which overexpress bcl-2 or bcl-xlong (bcl-xL) in the mammary gland. Expression of bcl-2 will be controlled by the WAP promoter. Expression of bcl-xL will be conditionally controlled using the tetracycline responsive gene expression system. An adenovirus vector will be used to express bcl-xshort (bcl-xS) in mammary glands from transgenic mice placed in organ culture. Specific aims: 1. Test if simple overexpression of survival inducers bcl-2 or bcl-xL in conjunction with Tag results in immediate resistance to p53-independent apoptosis. Compare results of bc1-xL and bcl-2 overexpression. 2. Analyze the frequency of apoptosis when the death inducer bcl-xS is expressed in tissue which is either sensitive or resistant to p53-independent apoptosis. 3. Determine if overexpression of bcl-2 or bcl-xL with Tag during tumorigenesis alters the pattern or levels of expression of bcl-2 related genes or non-bcl-2 related apoptosis pathway genes. 4. Determine if overexpression of bcl-2 and bcl-xL influences expression patterns of other cellular genes known to be differentially expressed in Tag induced breast cancers. 5. Establish the biological significance of dysregulated expression of bcl-2 related genes in breast tumorigenesis.