Evaluation of a new dual-specificity promoter for selective induction of apoptosis in breast cancer cells

The conditional expression of lethal genes in tumor cells is;l promising ge ne therapy approach for the treatment of cancer. The identification of prom oters that are preferentially active in cancer cells is the starting point for this strategy. The combination of tissue-specific and tumor-specific el ements offers the possibility to artificially develop such promoters. We de scribe the construction and characterization of a hybrid promoter for trans criptional targeting of breast cancer. In many cases, breast cancer cells r etain the expression of estrogen receptors, and most solid tumors suffer fr om hypoxia as a consequence of their abberent vascularization. Estrogen res ponse elements and hypoxia-responsive elements were combined to activate tr anscription in cells that present at least one of these characteristics. Wh en a promoter containing these elements is used to control the expression o f the pro-apoptotic gene harakiri, the induction of cell death can be activ ated by estrogens and hypoxia, and inhibited by antiestrogens such as tamox ifen. Finally, we show evidence that these properties are maintained in the context of an adenoviral vector (AdeHhrk). Therefore, infection with this virus preferentially kills estrogen receptor - positive breast cancer cells , or cells growing under hypoxic conditions. We propose the use of this pro moter for transcriptional targeting of breast cancer.