@article{082f5d7e100447aabe6516d6989fae22,
title = "Dynamin impacts homology-directed repair and breast cancer response to chemotherapy",
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.",
author = "Chernikova, {Sophia B.} and Nguyen, {Rochelle B.} and Truong, {Jessica T.} and Mello, {Stephano S.} and Stafford, {Jason H.} and Hay, {Michael P.} and Andrew Olson and Solow-Cordero, {David E.} and Wood, {Douglas J.} and Solomon Henry and {von Eyben}, Rie and Lei Deng and Gephart, {Melanie Hayden} and Asaithamby Aroumougame and Claudia Wiese and Game, {John C.} and Bal{\'a}zs Gy{\H o}rffy and {Martin Brown}, J.",
note = "Funding Information: We thank M. Jasin, S.N. Powell, L.H. Thompson, S.J. Knox, J.E. Price, and Z. Shen for the gifts of cell lines and constructs used in the study. We thank O.V. Razorenova (University of California, Irvine, California, USA) for valuable manuscript critiques, and Jason Wu from the Stanford High-Throughput Bioscience Center (Stanford University, Stanford, California, USA) for technical assistance with the chemical screen. This work was supported by NIH grants P01-CA067166 to JMB, ES021454 to CW, K08-NS901527 to MHG, and R01-AG053341 to AA. High-resolution microscopy images were obtained with Stanford Neuroscience Microscopy Service, supported by NIH NS069375. Stanford Cancer Institute Research Database was supported by National Cancer Institute Cancer Center Support Grant 5P30CA124435 and Stanford NIH/National Center for Research Resources Clinical and Translational Science Award UL1 RR025744. BG was supported by grant NVKP_16-1-2016-0037 of the National Research, Development and Innovation Office, Hungary. LD was supported by the China Scholarship Council. Publisher Copyright: Copyright 2018, American Society for Clinical Investigation.",
year = "2018",
month = dec,
day = "3",
doi = "10.1172/JCI87191",
language = "English (US)",
volume = "128",
pages = "5307--5321",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "12",
}