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 9

DNM2 expression predicts chemotherapy outcome for ER– breast cancer patients.

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DNM2 expression predicts chemotherapy outcome for ER– breast cancer pat...
(A) DNM2 expression in 1,000 systemically untreated patients, 752 patients treated with endocrine therapy, and 274 breast cancer patients treated with chemotherapy. *P < 0.05, ANOVA. (B) DNM2 expression levels are not significantly different between chemotherapy-treated ER+ and ER− tumors. P = 0.167, Mann-Whitney test. (C and D) Decreased DNM2 is associated with better chemotherapy outcome in ER− patients. Patients were split by median expression of DNM2 over the entire breast cancer data set (3,455 patients). Patients with higher than median expression of DNM2 are denoted in red, and those with lower than median expression of DNM2 are in black. Note the hazard ratio increase in the ER−, but not in the ER+, group. (C) Kaplan-Meier analysis of 105 patients with ER+ breast tumors treated with chemotherapy and 169 patients with ER− breast tumors treated with chemotherapy. (D) Kaplan-Meier analysis of 125 patients with BLBC and 76 patients with TNBC. (E) Longer disease-free survival after chemotherapy is associated with lower tumor DNM2 levels at the time of chemotherapy in ER− patients, but not in ER+ patients. Patients diagnosed with disease recurrence at the time of follow-up are designated as “Relapse,” and those remaining disease-free at the time of follow-up as “No relapse.” (F) Longer disease-free survival after chemotherapy is associated with lower tumor DNM2 levels at the time of chemotherapy in TNBC patients. Box plot: TNBCs that relapse during the first 3 years after treatment have significantly higher DNM2 than those that do not relapse or relapse later. (E and F) Linear regression analysis: P < 0.05 indicates that the slope is significantly non-zero. (A, B, and F) The boxes and whiskers contain points within the 25th to 75th and the 5th to 95th percentiles, respectively.