Our laboratory studies the role of cell cycle machinery in normal cell proliferation and in oncogenesis using mouse genetic, genomic, proteomic and systems biology approaches.
Cyclins and their catalytic partners, cyclin-dependent kinases (CDKs) are members of the core cell cycle machinery. This machinery has been conserved from yeast to humans, and it drives cell division. Consistent with their growth-promoting roles, overexpression of cyclins is seen in many human cancers. For example, cyclin D1 gene is amplified, and the protein overexpressed in the majority of human breast cancers.
In order to study the molecular function of particular cyclins in development and in cancer, we generated knockout mouse strains lacking individual cyclins, “knock-in” strains that cripple specific molecular functions of cyclins or substitute one cyclin with another, mice combining different epistatic mutations (loss of cyclin D1 and p27Kip1). These studies allowed us to decipher the function of particular cyclins in development. We also started to analyze the function of cell cycle proteins in neoplasia. Together with Dr. Hinds' laboratory (Tufts University) we found that changing a single nucleotide in the mouse genome (within the cyclin D1 gene) renders mice resistant to breast cancers. We also demonstrated that mice lacking cyclin D1, or mice lacking catalytic partner of cyclin D1, CDK4, were completely resistant to breast cancers triggered by a particular oncogenic event (overexpression of ErbB2 oncoprotein). We went on to show that the ErbB2?cyclin D1 pathway operates in a subset of human cancers. These findings led to clinical trials in which patients with ErbB2 overexpression are treated with CDK inhibitors.
We are extending this work in several directions. We are generating novel knockout mouse strains. We are combining the emerging genomic and proteomic technologies and with systems biology computational approaches to understand the function of the core cell cycle machinery in mouse development and in neoplasia. Moreover, we are extending these genomic and proteomic screens to human cancer cells.
Dept. of Cancer Biology, Smith Bldg., Rm. 922A
450 Brookline Ave.
Boston, MA 02215