Abstract
In this study, we first describe expression of the paired domain transcription factor PAX2 in the normal and cancerous human breast, then demonstrate in a murine model a novel function for PAX2 in the regulation of progesterone stimulation of secondary ductal growth. In human mammary tissue, PAX2 expression was coincident with sub-populations of mammary ductal cells, some of which possessed an undifferentiated histiotype, and was also found in >50% of the human breast tumors surveyed (n=38). In the mouse, mammary parenchyma with a targeted deletion of PAX2 developed normal ductal systems when grafted into wild-type host mammary fat pads, but failed to undergo higher order side-branching and lobular development in response to progesterone. A previously unsuspected PAX2/WT1 (Wilms' tumor suppressor gene) regulatory axis in the mammary gland was also indicated. Using RT–PCR, a significant reduction in WT1 mRNA expression was detected in the PAX2 mutant glands compared to wild-type counterparts and double-antibody immunohistochemistry detected the co-localization of PAX2 and WT1 in the nuclei of normal and cancerous breast cells. These data indicate a role for PAX2 (and possibly WT1) in the regulation of the progesterone response of the mature mammary gland. The potential contribution of PAX2 to breast tumor pathogenesis is discussed.
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Acknowledgements
We thank Drs J Snyder and KR O'Keefe (Dominican Hospital, Santa Cruz); Mr D Albritton, Ms P Huerta and Ms E Olson (University of California, Santa Cruz); Dr S Ethier (University of Michigan Breast Tissue Bank) for obtaining breast tissue samples and Drs Charles W Daniel, Daniel Medina and Charles Roberts Jr. for helpful suggestions and review of the manuscript. This work was supported by National Institutes of Health Grants DK-48883 (to Charles W Daniel, Santa Cruz) and D-54740 (to GR Dressler), Department of the Army Grant DAMD17-94-J-4230 (Charles W Daniel) and a gift from the Milton Meyer Foundation (to GB Silberstein).
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Silberstein, G., Dressler, G. & Van Horn, K. Expression of the PAX2 oncogene in human breast cancer and its role in progesterone-dependent mammary growth. Oncogene 21, 1009–1016 (2002). https://doi.org/10.1038/sj.onc.1205172
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DOI: https://doi.org/10.1038/sj.onc.1205172
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