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.
| Identifer | oai:union.ndltd.org:ADTP/242693 |
| Date | January 2007 |
| Creators | Caldon, Catherine Elizabeth, Garvan Institute of Medical Research, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Garvan Institute of Medical Research |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Catherine Elizabeth Caldon, http://unsworks.unsw.edu.au/copyright |
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