A feature of neoplastic cells is that mutations in the key intermediates of TGF-β signaling contribute to the loss of sensitivity to its anti-tumor effects. The role of SMAD3 and SMAD4 germline mutations in breast cancer predisposition is currently unclear. To address this, mutation analysis of the Mad-Homology 2 domains in 408 breast cancer cases and 710 controls recruited by the Breast Cancer Family Registry (BCFR) was performed using Denaturing High-Pressure Liquid Chromatography. This study identified 23 distinct intronic variants, and three coding variants c.1214T>C, c.1478G>A, and c.1701A>G in SMAD4. No aberrant splicing was observed, but qPCR analysis and tissue expression data showed significantly elevated SMAD3 expression relative to controls (p<0.05). For SMAD4, c.1478G>A from a familial breast cancer case showed a 5-fold expression change. Taken together, inactivating alterations are not driving tumorigenesis. Rather, aberrant germline expression provides novel insight into SMAD3 and SMAD4’s roles in breast cancer predisposition.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/33713 |
| Date | 03 December 2012 |
| Creators | Tram, Eric |
| Contributors | Ozcelik, Hilmi |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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