Research Abstract

The proliferation of mammalian cells is tightly controlled by numerous external signals. After they are received by the cells, these growth-promoting or growth-inhibitory signals are transmitted to the so-called cell-cycle machinery operating in the nucleus. The cell-cycle machinery is present in every single cell, and it can be thought of as the molecular engine that drives cell proliferation. The key components of this machinery are proteins termed cyclins. Abnormal expression of cyclins is seen in a great number of human cancers. For example, more than 50% of human breast cancers contain highly elevated levels of a particular cyclin protein, termed cyclin D1. Importantly, because agents that antagonize this cyclin have been shown to shut off the proliferation of breast cancer cells grown in vitro, overexpression of cyclin D1 seems to play a causative role in mammary tumorigenesis.

To understand the role played by these various cyclin proteins in normal development and in cancer, we generated several genetically engineered 'knockout' mouse strains lacking different cyclin proteins. We found that each of these proteins is required for proliferation in a very narrow, highly specific sets of tissues. For example, we discovered that cyclin D1-deficient mice develop hormone-insensitive mammary glands. Hence, the normal, physiologic role for cyclin D1 is to drive hormone-induced mammary epithelial proliferation, while overexpression of the very same cyclin plays a causative role in human breast cancers.

We are currently using these knockout strains, and cells derived from them, as tools to study the role of particular cyclin proteins in normal cell proliferation and in oncogenesis of breast cancers, in particular. Moreover, we are generating novel mutant mouse strains that will help explain the role of cell-cycle machinery at the organismal, cellular, and molecular levels.