Dynamin impacts homology-directed repair and breast cancer response to chemotherapy.

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dc.contributor.author Chernikova, Sophia B en
dc.contributor.author Nguyen, Rochelle B en
dc.contributor.author Truong, Jessica T en
dc.contributor.author Mello, Stephano S en
dc.contributor.author Stafford, Jason H en
dc.contributor.author Hay, Michael en
dc.contributor.author Olson, Andrew en
dc.contributor.author Solow-Cordero, David E en
dc.contributor.author Wood, Douglas J en
dc.contributor.author Henry, Solomon en
dc.contributor.author von Eyben, Rie en
dc.contributor.author Deng, Lei en
dc.contributor.author Gephart, Melanie Hayden en
dc.contributor.author Aroumougame, Asaithamby en
dc.contributor.author Wiese, Claudia en
dc.contributor.author Game, John C en
dc.contributor.author Győrffy, Balázs en
dc.contributor.author Brown, J Martin en
dc.date.accessioned 2019-02-28T21:50:54Z en
dc.date.issued 2018-12 en
dc.identifier.citation Journal of clinical investigation 128(12):5307-5321 Dec 2018 en
dc.identifier.issn 0021-9738 en
dc.identifier.uri http://hdl.handle.net/2292/45644 en
dc.description.abstract After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries The Journal of clinical investigation en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.subject CHO Cells en
dc.subject Animals en
dc.subject Humans en
dc.subject Cricetulus en
dc.subject Mice en
dc.subject Mice, Nude en
dc.subject Dynamins en
dc.subject Antineoplastic Agents en
dc.subject Xenograft Model Antitumor Assays en
dc.subject Female en
dc.subject Recombinational DNA Repair en
dc.subject Triple Negative Breast Neoplasms en
dc.title Dynamin impacts homology-directed repair and breast cancer response to chemotherapy. en
dc.type Journal Article en
dc.identifier.doi 10.1172/JCI87191 en
pubs.issue 12 en
pubs.begin-page 5307 en
pubs.volume 128 en
dc.rights.holder Copyright: American Society for Clinical Investigation en
pubs.end-page 5321 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.subtype Research Support, N.I.H., Extramural en
pubs.elements-id 758775 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Auckland Cancer Research en
pubs.org-id Science en
pubs.org-id Science Research en
pubs.org-id Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 1558-8238 en
pubs.record-created-at-source-date 2018-10-30 en
pubs.dimensions-id 30371505 en


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