Cyclin D1 belongs to a family of three proteins (termed cyclin D1, D2, and D3) that control cell proliferation. Abnormally high levels of cyclin D1 are seen in the majority of human breast cancers. Studies in the test tube have shown that compounds that cripple cyclin D1 function can shut off the proliferation of breast cancers cells. For this reason, a specific anti-cyclin D1 therapy for human breast cancers might be an attractive possibility. However, until very recently, cyclin D1 was thought to be vital for proliferation of nearly all human cell types.
We have challenged this dogma by creating mice lacking cyclin D1 using genetic engineering techniques. Surprisingly, we have found that these cyclin D1-deficient mice develop essentially normally, with the exception of mammary glands that fail to undergo normal proliferation when the mice become pregnant. Thus, these studies revealed that cyclin D1 is dispensable for the proliferation of all adult mouse tissues except for the mammary glands.
This unexpected finding, together with the well-documented role for cyclin D1 in human breast cancers, may encourage the development of therapeutic agents that specifically antagonize this cyclin. Such agents might prove to be highly selective in shutting off the proliferation of breast cancer cells while sparing all other tissues.
As a fist step toward a potential anti-cyclin D1 therapy for human breast cancers, we wish to test if the loss of cyclin D1 protects mice from breast cancers. To address this question, we will cross cyclin D1-deficient mice with several breast cancer-prone mouse strains and we will score the resulting progeny for the development of breast cancers.
In the second set of experiments, we will ask if cyclin D1 plays a unique role in mammary development and in breast cancer due to its special ability to bind breast-specific proteins. To address this question, we will use a very novel "knock-in" technology of mouse genetic engineering. This method permits us to replace one protein with another. Thus, we will generate mutant "knock-in" mice lacking cyclin D1 but containing instead a highly related member of the cyclin D family, cyclin D2 (cyclin D2 is normally not present in mammary glands). By studying mammary gland development of these "knock-in" mice, we will determine whether cyclin D2 can replace cyclin D1 in driving normal mammary proliferation. If it cannot, we would reason that cyclin D1 binds to a specific set of mammary proteins.
Secondly, we will ask if cyclin D2 can replace cyclin D1 in driving the proliferation of breast cancer cells. To answer this question, we will cross "knock-in" mice with several strains of breast cancer-prone mice, and we will score the breast cancer incidence in the resulting progeny. Again, if we find that cyclin D2 is unable to replace cyclin D1 in driving breast cancer cell proliferation, we will conclude that cyclin D1 plays a unique role in breast cancer due to its special ability to bind specific proteins. In the future, the identification of these proteins will help to understand the molecular basis of human breast cancer.