Expression of the PAX2 oncogene in human breast cancer and its role in progesterone-dependent mammary growth.
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.
Silberstein
Gary B
GB
Department of Molecular, Cell and Developmental Biology, Sinsheimer Laboratories, University of California, Santa Cruz, CA 95064, USA. silberstein@biology.ucsc.edu
Dressler
Gregory R
GR
Van Horn
Katharine
K
D000818:Animals; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009857:Oncogenes; D051762:PAX2 Transcription Factor; D011374:Progesterone / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human; C497319:Pax2 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D025721:WT1 Proteins; D011374:Progesterone