Nancy Ellen Davidson, M.D.
Our laboratory focuses on translational research in the field of breast cancer, the most common malignancy in American women. Our interests are driven by scientific questions that have implications for biology, diagnosis, prevention, and/or treatment. A critical molecule in breast cancer biology and treatment is the estrogen receptor alpha (ER). ER is a member of the steroid receptor super-family; it transduces the signaling of the hormone, estrogen, in estrogen-responsive tissues. Some breast cancers express ER; these are most likely to respond to endocrine therapies such as the anti-estrogen, tamoxifen, or strategies to lower estrogen levels. But about one-quarter of breast cancers do not express ER. Our studies have suggested that this may be related to silencing of the gene by epigenetic mechanisms such as methylation of the CpG island in the ER promoter region or modulation of histone acetylation. Current work is evaluating the nature of the repressive complex at the ER promoter; the repertoire of genes that are reexpressed with demethylating agents, histone deacetylase inhibitors, or both; and the utility of these approaches in animal models of ER-negative breast cancer.
A second line of research is evaluating the polyamine metabolic pathway as a target for treatment and prevention of breast cancer. The small cationic polyamines play a role in a number of critical cellular functions and dysregulation of the polyamine metabolic pathway is a feature of many cancers, including breast cancer. Ongoing work is assessing the ability of a series of polyamine analogs to inhibit proliferation and promote apoptosis of human breast cancer cell lines. Mechanisms of action for response and resistance are also under study. It is our hope to develop these agents for clinical intervention for breast cancer treatment and prevention in women; indeed our first compound has undergone clinical testing.
- Yan L, Nass SJ, Smith D, Nelson WG, Herman JG, and Davidson NE. Specific inhibition of DNMT1 by antisense oligonucleotides induces re-expression of estrogen receptor alpha (ER) in ER-negative human breast cancer cell lines. Cancer Biology and Therapy 2:552-6, 2003.
- Keen JC, Garrett-Mayer, Pettit C, Mack KM, Manning J, Herman JG, and Davidson NE. Epigenetic regulation of protein phosphatase 2A (PP2A), lymphotactin (XCL1), and estrogen receptor alpha (ER) expression in human breast cancer cells. Cancer Biology and Therapy, in press.
- Huang Y, Hager ER, Phillips DL, Dunn VR, Hacker A, Frydman B, Kink JS, Valasinas AL, Reddy VK, Marton LJ, Casero Jr RA, and Davidson NE. A novel polyamine analog inhibits growth and induces apoptosis in human breast cancer cells. Clinical Cancer Res 9:2769-77, 2003.
- Huang Y, Kee JC, Hager E, Smith R, Hacker A, Frydman B, Valasinas AL, Reddy VK, Marton LJ, Casero Jr RA, and Davidson NE. Regulation of polyamine analogue cytotoxicity by c-Jun in human MDA-MB-435 cancer cells. Molecular Cancer Res 2:81-8, 2004.
- Huang Y, Pledgie A, Casero Jr RA, and Davidson NE. Molecular mechanisms of polyamine analogs in cancer cells. Anti-Cancer Drugs, in press.