287. mda-7: A Remedy for Oncogene Addiction in Breast Cancer?

Abstract

The concept of |[ldquo]|oncogene addiction|[rdquo]| has been proposed to support the rationale for development of molecularly targeted therapies. It is clear that acquisition of genetic mutations results in dysregulation of oncogenic signaling pathways in tumor cells, and recent studies have indicated that persistence of these dysregulated oncogenes is essential for maintaining the tumorigenic phenotype. We evaluated the role of mda-7 gene transfer in oncogene-addicted breast cancer cells. Current therapies used in the treatment of breast cancer are limited by systemic toxicity, rapid drug metabolism and intrinsic and acquired drug resistance. We previously showed that adenoviral mediated transfer of the melanoma differentiation-associated gene-7 (mda-7) elicits growth inhibition and apoptosis in various tumor types. Here, we evaluate the effects of Ad-mda7, alone and in combination with other therapies, against a panel of nine breast tumor cell lines and their normal counterparts; we report tumor-selective p53-independent growth inhibition, G2/M cell cycle arrest, and apoptosis induction by Ad-mda7. In vivo, Ad-mda7 induced p53-independent tumor growth inhibition (p<0.004) in multiple xenograft models. We then evaluated the combination of Ad-mda7 with agents commonly used to treat breast cancer: radiotherapy (XRT), Tamoxifen, Taxotere, Adriamycin, and Herceptin. These agents exhibit diverse modes of action, including formation of bulky adducts, inhibition of DNA replication (Adriamycin, XRT), damage to microtubules (Taxotere), non-steroidal estrogen antagonists (Tamoxifen), or Her2/neu receptor blockade (Herceptin). Treated with conventional anti-cancer drugs or radiation, MDA-7-expressing cells display additive or synergistic cytotoxicity and apoptosis that correlates with decreased BCL-2 expression and BAX up-regulation. In vivo, animals that received Ad-mda7 and XRT underwent significant reduction of tumor growth (p<0.002). This is the first report of the synergistic effects of Ad-mda7 combined with chemotherapy or radiotherapy on human breast carcinoma cells, and suggests that mda-7 gene transfer can overcome the oncogene addiction observed in breast cancer.