The Influence of Stromal Transforming Growth Factor-(beta) Receptor Signaling on Mouse Mammary Neoplasia
Annual rept. 1 Aug 2001-31 Jul 2002
CINCINNATI UNIV OH
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Disruption of the TGF-BETA signaling pathway in the mammary stroma results in aberrant ductal morphogenesis. Our laboratory has developed transgenic mice that express a Zn2 inducible, kinase-defective dominant-negative TGF-BETA type II receptor in the mammary stroma MTR28. Female mice expressing the dominant-negative receptor demonstrated increased lateral branching, suggesting TGF-BETA signaling in the stroma has important effects on epithelial morphogenesis. Recent evidence has accumulated implicating a role for the stroma in regulating tumor formation. To determine if loss of responsiveness to TGF-BETA in the stroma effects tumor development transgenic and wild type mice were given pituitary isografts followed by zinc water and either left untreated control or treated with 7,12-dimethylbenz a anthracene DMBA. Several tumors developed in the wild type group on a full regiment pituitary isograft, zinc and DMBA while only one tumor has arisen in the control group. To date, only two tumors have arisen in the transgenic mice on a full regiment. To identify genes regulated by TGF-BETA in the mammary stroma, filter and gene chip microarrays were screened, also subtracted cDNA libraries produced by suppression subtractive hybridization SSH were arrayed on glass slides. The filter based and commercial gene chip microarrays identified genes expressed in the mammary stroma and directly regulated by TGF-BETA-p. The genes were verified by Northern analysis and in situ hybridization. The expression of several categories of genes were affected by loss of TGF-psignaling as determined by sequence analysis of the SSH libraries.
- Anatomy and Physiology
- Medicine and Medical Research