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Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers

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dc.contributor.author Berge, Elisabet Ognedal
dc.contributor.author Knappskog, Stian
dc.contributor.author Geisler, Stephanie
dc.contributor.author Staalesen, Vidar
dc.contributor.author Pacal, Marec
dc.contributor.author Børresen-Dale, Anne-Lise
dc.contributor.author Puntervoll, Pål
dc.contributor.author Lillehaug, Johan
dc.contributor.author Lønning, Per Eystein
dc.date.accessioned 2011-04-15T09:13:20Z
dc.date.available 2011-04-15T09:13:20Z
dc.date.issued 2010-07-01
dc.identifier.citation Molecular Cancer 2010, 9:173 en_US
dc.identifier.uri http://dx.doi.org/10.1186/1476-4598-9-173
dc.identifier.uri http://hdl.handle.net/1956/4672
dc.description.abstract Background The tumor suppressor pRb plays a key role regulating cell cycle arrest, and disturbances in the RB1 gene have been reported in different cancer forms. However, the literature reports contradictory findings with respect to a pro - versus anti - apoptotic role of pRb, and the consequence of alterations in RB1 to chemotherapy sensitivity remains unclear. This study is part of a project investigating alterations in pivotal genes as predictive factors to chemotherapy sensitivity in breast cancer. Results Analyzing 73 locally advanced (stage III) breast cancers, we identified two somatic and one germline single nucleotide changes, each leading to amino acid substitution in the pRb protein (Leu607Ile, Arg698Trp, and Arg621Cys, respectively). This is the first study reporting point mutations affecting RB1 in breast cancer tissue. In addition, MLPA analysis revealed two large multiexon deletions (exons 13 to 27 and exons 21 to 23) with the exons 21-23 deletion occurring in the tumor also harboring the Leu607Ile mutation. Interestingly, Leu607Ile and Arg621Cys point mutations both localize to the spacer region of the pRb protein, a region previously shown to harbor somatic and germline mutations. Multiple sequence alignment across species indicates the spacer to be evolutionary conserved. All three RB1 point mutations encoded nuclear proteins with impaired ability to induce apoptosis compared to wild-type pRb in vitro. Notably, three out of four tumors harboring RB1 mutations displayed primary resistance to treatment with either 5-FU/mitomycin or doxorubicin while only 14 out of 64 tumors without mutations were resistant (p = 0.046). Conclusions Although rare, our findings suggest RB1 mutations to be of pathological importance potentially affecting sensitivity to mitomycin/anthracycline treatment in breast cancer. en_US
dc.publisher BioMed Central en
dc.rights Copyright 2010 Berge et al; licensee BioMed Central Ltd. en_US
dc.rights.uri http://creativecommons.org/licenses/by/2.0 en_US
dc.title Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers en_US
dc.type Peer reviewed en_US
dc.type Journal article en_US
dc.subject.nsi VDP::Mathematics and natural science: 400 en_US
dc.rightsHolder Berge et al. en_US
dc.type.version publishedVersion en_US


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Copyright 2010 Berge et al; licensee BioMed Central Ltd. Except where otherwise noted, this item's license is described as Copyright 2010 Berge et al; licensee BioMed Central Ltd.

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