Abstract 1513: Functional analysis ofTGFBR1mutations in breast cancer associated fibroblasts
Cancer Research(2012)
摘要
The TGFBR1*6A variant consists of a GCG repeat deletion resulting in a three-alanine deletion in the TGFBR1 coding region which has been linked to breast cancer risk. We have screened 30 breast cancer cell lines including: 20 epithelial (2 from normal breast) and 10 CAFs (2 from normal breast) for the presence of this mutation. Initial screening indicates that 45% of the epithelial cell lines screened harbor the *6A mutation. Of the 8 fibroblast screened 67% harbored TGFBR1*6A. The following CAF cell lines were used for the remainder of our functional studies: Hs748 (9A/9A), Hs841.T (9A/6A) and Hs742.T (6A/6A) genotypes. CAFs were treated with 100pM TGF-β resulting in decreased growth inhibitory response of 20% for Hs742.T (*6A/*6A) cells when compared to Hs841.T (9A/*6A) cells with 42% inhibition. Invasion assays, using a matrigel-coated Boyden Chamber, indicated a higher invasive capacity for Hs841.T (9A/6A) fibroblast cell line than in the Hs742.T (6A/6A) or Hs748.T (9A/9A). Western blot analysis was used to determine cell differentiation status. Cells which harbor TGFBR1*6A showed an increased expression of α-sma when compared to the WT fibroblasts indicating progression to a more aggressive myofibroblast phenotype. Studies are underway to reproduce these data in additional CAF cell lines, however, this preliminary data suggest that TGFBR1*6A enhances breast cancer development by enhancing tumor-associated fibroblast oncogenic properties in addition to its direct effect on breast tumor cells. TGF-β signaling was altered in TGFBR1*6A cells which may alter normal tumor-stromal signaling pathways. Future studies, using primary cell lines derived from a transgenic mouse model harboring the TGFBR1*6A allele will provide an optimal system to dissect the functional effects of this mutation in tumor and stromal cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1513. doi:1538-7445.AM2012-1513
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关键词
functional analysis oftgfbr1mutations,breast cancer
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