Molecular Carcinogenesis

The goal of the Molecular Carcinogenesis Program is to discover mechanisms determining the multi-step process by which normal cells become malignant. Members investigate biological processes that facilitate or impede the progressive molecular and cellular alterations in this evolution to cancer.

Program research is organized around three areas of emphasis:

1. DNA Repair, Genetic Stability and Checkpoint Regulation
2. Modulation of Carcinogenesis, and
3. Epithelial Cell Growth and Carcinogenesis.

Areas of emphasis include

• molecular mechanisms of DNA repair
• DNA replication
• cell cycle checkpoint control
• genetics of cancer cell evolution
• discovery of tumor suppressor genes, and
• mechanisms by which each of these affects cell growth and differentiation.

There is particular interest in the interaction between stromal and epithelial cells in tissues and how alterations in their homeostatic relationship contribute to cancer development.

Highlights of Program research include:

• the discovery by Dr. Tom Petes that the loss of ATM and ATR homologues, TEL1 and MEC1, result in telomeric fusions and translocations, the characterization of DNA nucleotide excision repair by Dr. Aziz Sancar, including isolation of constituent proteins, demonstration of their function in vitro, and their structural relationships at DNA damage sites
• the discovery of the mechanism of renal carcinogenesis by unleaded gasoline by Dr. James Swenberg, which lead the EPA to incorporate mechanisms in its estimation of human cancer hazards of carcinogens, and
• the demonstration by Dr. David G. Kaufman that endometrial epithelial cell growth in response to estrogen is mediated by paracrine factor secreted by stromal cells and that progesterone treatments ameliorate the effect of estrogen as an endometrial carcinogen.

The Program adds value to the Center by facilitating collaborative research much of which is translational in nature.

The Program is led by David G. Kaufman, M.D., Ph.D., leader for the past 15 years. He is a physician scientist with a national reputation in carcinogenesis research and a laboratory program in endometrial carcinogenesis. In 2003, the Program had 20 members. The aggregate research funding of this highly successful group in 2003 was $9.8M, including $1.6M in NCI research and NCI all funding. In 2002, the total number of publications was 93; where 19% of the publications were intra-programmatic and 12% were inter-programmatic. Future plans include integration of hepatic researchers into a liver cancer group and recruitment of new investigators in epithelial carcinogenesis and stromal-epithelial interaction.