Prognostic Value of Telomere DNA Content in Ductal Carcinoma in Situ

摘要

Critically shortened telomeres cause genomic instability both in vivo and in vitro and thus drives changes in gene expression Reduced telomere DNA content (TC) is associated with reduced survival in breast and prostate cancers We hypothesized that TC could be a unique prognostic marker in DCIS The goals of this project were: I) determine if TC can be used to predict outcome in a retrospective study of DCIS, 2) determine if alterations in telomere homeostasis can induce changes in gene expression that could be the basis of novel prognostic markers TC has been determined in microdissected tissues enriched for DCIS or histologically normal adjacent tissues from a cohort of non-recurrent DCIS Efforts to obtain a recurrent DCIS samples are ongoing. A model system has been developed to examine gene expression changes in response to alterations in telomere homeostasis Telomere binding proteins TRF2, a dominant negative allele of TRF2, and hTERT were expressed in primary human mammary epithelial cell populations from four donors Microarrays were performed on these cell populations Over-expression of TRF2wt and to a lesser extent, TRF2dn induces the expression of Cox 2 mRNA (p=0.05) and protein in an Activin A-dependent manner Activin A, a member of the TGF-beta superfamily, induces the phosphorylation and activation of both p38 MAPK and Smad2/3. Both these proteins can affect the level of Cox 2 mRNA= Exogenous activin A results in an increase in activated p3B and Cox 2. Treatment of cells with the p38 inhibitor SB203580 leads to a decrease in Cox 2 protein In vivo, high Cox 2 expression is associated with reduced TC in DCIS (p>O=0009).