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Circadian mitotic rhythms in epithelial cells of human epidermis (Schevirg, 1959), rat cornea (Scheving,1967) and intestinal epithelium of the mouse (Sidgestad,1972) have been reported in the literature. It is the attempt of this investigation to determine the presence of a circadian rhythm governing the mitotic activity of hair follicle cells in neonatal white mice. The animals used were reared under closely controlled conditions of temperature, humidity, lighting and food. A total of forty-eight, three to four day old mice were used, with eight animals being sampled every four hours over a twenty-four hour period. Skin sections were removed and fixed in Bouins fluid. The tissues were dehydrated in alcohols, cleared in xylol and infiltrated and embedded in paraffin. The sectioned tissues were placed on glass slides, rehydrated and stained with hematoxylin and eosin. To assess the mitotic activity over the twenty-four hour period, cell counts within the follicles were made from the slides. For each animal, 1000 hair follicle cells were counted. Cells undergoing mitosis were identified and specific stages were tallied. These stages were 1) prophase, 2) metaphase, 3) anaphase-telophase and 4) unidentifiable cells. Photomicrographs were made to record the histology and demonstrate the mitotic activity.When the data was statistically analyzed, an analysis of variance test failed to show a significant difference among the mean values of dividing cells from animals sampled during the different time periods. However, the F value for metaphase favorably approaches the table F value for the conditions of this study.By far, the strongest data to support the existence of a circadian rhythm within the hair follicle cells of mice is demonstrated when the mean values for each of the mitotic cell categories are plotted against time for the twenty-four hour period. Metaphase shows peaks in activity at 6:00 a.m. and 10:00 p.m. A similar pattern is also seen for the unidentifiable cells. The peak mitotic activities for prophase, and anaphase-telophase was seen to occur at 10:00 p.m.

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Loss of proliferative control is a cornerstone of cancer development, induced by deregulation of mitogenic signalling, insensitivity to anti-proliferative signals and direct changes in cell cycle proteins. In breast cancer these alterations are frequently targeted through cyclins D1 and E, leading to defects in G1/S transition. I have investigated the role of two potential pro-proliferative oncogenes in breast cancer, id1 andwt1. Each protein promotes proliferation in distinct contexts, with unique consquences for breast cancer cells. Using a 3D culture model of non-transformed mammary epithelial cells, I identified that id1 undergoes downregulation via rapid proteosomal degradation and cytoplasmic relocalisation during mammary epithelial morphogenesis. Overexpression of Id1 led to an increase in acinar size via an increase in S phase, and wa dependent on the presence of an intact HLH domain in Id1. Co-expression with the proto-oncogene Bcl2 led to a more disorganised acinar structure, indicating that Id1 overexpression primed the cells for further oncogenic insult. Further, Id1 overexpression was unable to increase acinar size in cyclin D1-/- acini, indicating that Id1 is dependent on cyclin D1 for its proliferative effects. Overall these data identified Id1 as capable of altering the proliferation of normal mammary epithelial cells, a crucial step in early breast carcinogenesis. Wt1 was originally identified as a tumour suppressor, but our data lends support to Wt1 acting as an oncogene in breast cancer. Wt1 is expressed highly in a range of breast cancer cell lines, and is strongly regulated by progestins. Using siRNA, we identified that Wt1 is likely to be a molecular intermediary of progestin as the downregulation of Wt1 mimics a subset of progestin effects on cell proliferation and lipid synthesis. Conversely, the overexpression of the major Wt1 isoform, Wt1 (+/+), led to attenuation of progestin-induced differentiation and growth arrest via maintenance of cyclin D1 levels. The effects of Wt1 overexpression were specific to progestins, and did not affect the actions of anti-estrogens or androgens. Consequently the overexpression of Wt1 (+/+) may disrupt the endocrine response in mammary epithelial cells, and contribute to excess proliferation and failure to differentiate during breast oncogenesis.