Circadian Clock and Cell Cycle Gene Expression in Mammary Glands

David Earnest, Ph.D. and Weston W. Porter, Ph.D.
Texas A&M University
P30ES09106

Background: A tiny region in the brain, known by the seemingly incongruous name the suprachiasmatic nucleus (SCN) regulates the timing of mammals including humans. Within this pin-head sized set of neurons is a biological clock that keeps track of the time of day, seasons of the year, and makes sure our bodies and brains are in step. Scientists know that the SCN is a biological clock because when it is surgically destroyed in an experimental animal, rhythms in sleep and wake cycles fade away. Interestingly, the animal, minus its SCN, runs, eats and drinks the same total amount each 24 hours, but these activities are now randomly distributed throughout the day and night. Sunlight and darkness serve to reset the biological clock every day and keep us on a 24-hour cycle.

The expression of genes controlling the biological clock is not limited to the SCN, but is found in many cells and tissues including the mammary gland. The mammary gland is unique because most of its development occurs after puberty and it goes through cycles of cell proliferation, differentiation, and regression coinciding with pregnancy, lactation, and involution. The expression of clock genes in mammary tissue has not been thoroughly explored. Recent studies have shown that disruptions in the sleep wake cycle in female shift workers lead to increased risk of breast cancer presumably by altering circulating levels of the pineal gland hormone melatonin. The purpose of the study reported here was to determine whether developmental changes in clock gene expression occur within mammary epithelial-derived cell lines and mouse mammary tissues.

Advance: An NIEHS-supported research team at Texas A&M University has discovered a differentiation-dependent profile of mammary epithelial cells. In a mouse mammary epithelial cell line, differentiated cells, cells that have fully matured to their final state, expression of the clock genes Per1 and Bmal1 was elevated, but in undifferentiated cells, Per2 was elevated. These changes were consistent with those seen in actual mouse mammary tissue. In both the cells in culture and mammary tissue, elevated Per2 expression was associated with expression of c-Myc and Cyclin D1, cell cycle control genes commonly activated in a variety of human tumors including breast cancer.

Implications: The results of these studies show that circadian clock genes may play a role in mammary gland development and cellular differentiation. The patterns of gene expression also suggest that interactions between these genes and cell cycle control genes may have implications for not only mammary gland development but also the development of breast cancer.

Citation: Metz RP, Qu X, Laffin B, Earnest D, Porter WW. Circadian clock and cell cycle gene expression in mouse mammary epithelial cells and in the developing mouse mammary gland. Dev Dyn. 2006 Jan;235(1):263-71.