Dynamin impacts homology-directed repair and breast cancer response to chemotherapy
Sophia B. Chernikova, … , Balázs Győrffy, J. Martin Brown
Sophia B. Chernikova, … , Balázs Győrffy, J. Martin Brown
Published October 29, 2018
Citation Information: J Clin Invest. 2018;128(12):5307-5321. https://doi.org/10.1172/JCI87191.
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Research Article Oncology

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.

Authors

Sophia B. Chernikova, Rochelle B. Nguyen, Jessica T. Truong, Stephano S. Mello, Jason H. Stafford, Michael P. Hay, Andrew Olson, David E. Solow-Cordero, Douglas J. Wood, Solomon Henry, Rie von Eyben, Lei Deng, Melanie Hayden Gephart, Asaithamby Aroumougame, Claudia Wiese, John C. Game, Balázs Győrffy, J. Martin Brown

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Figure 8

Inhibition of DNM2 sensitizes cells in S/G2 phase and improves tumor response to cytotoxic therapy in an orthotopic mouse model.

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Inhibition of DNM2 sensitizes cells in S/G2 phase and improves tumor res...
(A) Dynasore increases radiation sensitivity of AA8 cells in S and S/G2 phases, but does not affect radiation sensitivity of G1-phase cells. Shown are means ± SDs (ranges) from n ≥ 2 MTS experiments. ANOVA: all groups were compared with the G1. **P < 0.01, ***P < 0.001. Cell cycle distribution is shown on the right. (B) DNM2 knockdown increases tumor sensitivity to cyclophosphamide (CPX) in an orthotopic model of TNBC. MDA-MB-231-BR3 cells with an inducible DNM2 knockdown (described in Figure 5F) were injected into mammary fat pads of female Nu/Nu mice and treated with 2 cycles of 100 mg/kg CPX on days 12, 14, and 16. After a 2-week break, mice were treated with CPX again (days 33, 35, and 37). DNM2 knockdown was induced by the addition of doxycycline to drinking water 3 days before and during CPX treatment. Symbols and error bars are means ± SEMs. Significance analysis: ANOVA, *P < 0.05. (C) Same experiment as in B analyzed using repeated-measures method. Post hoc pairwise comparisons were performed using a Tukey adjustment for multiple comparisons. P values are shown at day 49. See Supplemental Table 1 for details of the significance analysis.