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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 eng
dc.contributor.author Knappskog, Stian eng
dc.contributor.author Geisler, Stephanie eng
dc.contributor.author Staalesen, Vidar eng
dc.contributor.author Pacal, Marec eng
dc.contributor.author Børresen-Dale, Anne-Lise eng
dc.contributor.author Puntervoll, Pål eng
dc.contributor.author Lillehaug, Johan eng
dc.contributor.author Lønning, Per Eystein eng
dc.date.accessioned 2011-04-15T09:13:20Z
dc.date.available 2011-04-15T09:13:20Z
dc.date.issued 2010-07-01 eng
dc.identifier.citation Molecular Cancer 2010, 9:173 en_US
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 eng
dc.rights Attribution CC BY eng
dc.rights.uri http://creativecommons.org/licenses/by/2.0 eng
dc.title Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers eng
dc.type Peer reviewed eng
dc.type Journal article eng
dc.subject.nsi VDP::Mathematics and natural science: 400 eng
dc.rights.holder Copyright 2010 Berge et al; licensee BioMed Central Ltd.
dc.rights.holder Berge et al. eng
dc.type.version publishedVersion eng
bora.peerreviewed Peer reviewed eng
bibo.doi http://dx.doi.org/10.1186/1476-4598-9-173 eng
dc.identifier.doi http://dx.doi.org/10.1186/1476-4598-9-173


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