|Eileen Brantley, PhD|
|Assistant Professor, Physiology & Pharmacology|
|School of Medicine|
|University Faculty Profile|
Breast cancer represents the second leading cause of cancer death among women in industrialized nations. Agents such as Tamoxifen aid in improving survival in certain patients with hormone-responsive breast cancer. However, hormone-independent breast cancer is more aggressive and far less responsive to these agents. In addition, approximately 40% of patients with hormone receptor-dependent breast cancer do not respond to agents such as Tamoxifen and similar to those with hormone receptor-independent breast cancer, must turn to cytotoxic agents in an attempt to control the malignancy. These agents are prone to cause unappreciable side effects including the onset of cardiotoxicity and even secondary malignancies. Thus, the development of agents that target novel, hormone receptor-independent pathways to treat breast cancer is essential. Two novel candidate anticancer agents (5F 203 and Aminoflavone) are currently in Phase I clinical trials in the UK and US respectively. These candidate drugs demonstrate selective and potent anticancer activity in breast cancer cells irrespective of hormone receptor status. They differ from currently used clinical agents in that they activate the aryl hydrocarbon receptor signaling pathway to mediate their anticancer effects. We have recently determined that these agents modulate reactive oxygen species levels exclusively in cells sensitive to their anticancer effects and this modulation contributes to their overall mechanism of anticancer activity. We seek to further elucidate key players within signaling pathways that modulate oxidative stress and to characterize cross-talk interactions between these pathways and the aryl hydrocarbon receptor signaling pathway that ultimately result in growth suppression of malignant breast cancer cells.
1. McLean, L., Soto, U., Agama K., Francis, J., Jimenez, R., Pommier, Y., Sowers, L., and Brantley, E. Aminoflavone induces oxidative DNA damage and reactive oxygen species-mediated apoptosis in breast cancer cells. Int. J. Cancer. 2008 Apr; 122 (7):1665-1674. Epub 4 Dec 2007.
2. Brantley, E., Kohlhagen, G., Antony, S., Meng, LH., Agama K., Stinson, S.F., Sausville, E.A. and Pommier, Y. Anti-tumor drug candidate 2-(4-Aminophenyl)-5-fluorobenzothiazole induces single-strand breaks and DNA-protein cross-links in sensitive MCF-7 cells. Cancer Chemother Pharmacol. 2006 Jul; 58(1):62-72. Epub 6 Dec 2005.
3. Brantley, E., Patel, V., Hose, C., Ciolino, H.P., Yeh, G.C., Trapani, V., Stinson, S.F., Sausville, E.A. and Loaiza-Perez, A.I. The antitumor drug candidate 2-(4-amino-3-methylphenyl)-5-Fluorobenzothiazole activates NF-kB signaling in MCF-7 cells in response to DNA damage. Anticancer Drugs. 2005 Feb;16 (2):137-143.
4. Brantley, E., Trapani, V., Alley M.C., Hose, C.D., Bradshaw, T.D., Stevens, M.F.G.and Stinson, S.F. Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles are metabolized and bind to sub-cellular macromolecules in sensitive human cancer cells. Drug Metab Dispos. 2004 Dec;32(12):1392-401. Epub 8 Sep 2004.
5. Chua, M.-S., Kashiyama, E., Bradshaw, T.D., Stinson, S.F., Brantley, E., Sausville, E.A. and Stevens, M.F.G. Role of CYP1A1 in modulation of the antitumor properties of the novel agent 2-(4-Amino-3-methylphenyl) benzothiazole (DF 203, NSC 674495) in human breast cancer cells. Cancer Res. 2000,Sep;60(18):5196-203.