title: Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes.
abstract: Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT), and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility, and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons, and that the DIAPH3 network potentially reports taxane sensitivity in human tumors.
authors.affiliation: 1] Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048 [2] Urological Diseases Research Center, Boston Children's Hospital, Boston, MA 02115 [3] Department of Surgery, Harvard Medical School, Boston, MA 02115.
authors.forename: Samantha
authors.initials: S
authors.lastname: Morley
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Sungyong
authors.initials: S
authors.lastname: You
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Sara
authors.initials: S
authors.lastname: Pollan
authors.affiliation: Urological Diseases Research Center, Boston Children's Hospital, Boston, MA 02115.
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Choi
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: 1] Urological Diseases Research Center, Boston Children's Hospital, Boston, MA 02115 [2] Department of Surgery, Harvard Medical School, Boston, MA 02115.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Hager
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Steadman
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Spinelli
authors.affiliation: Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Rajendran
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Gertych
authors.affiliation: 1] Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048 [2] Urological Diseases Research Center, Boston Children's Hospital, Boston, MA 02115 [3] Department of Surgery, Harvard Medical School, Boston, MA 02115.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Kim
authors.affiliation: 1] Urological Diseases Research Center, Boston Children's Hospital, Boston, MA 02115 [2] Department of Surgery, Harvard Medical School, Boston, MA 02115.
authors.forename: Rosalyn M
authors.initials: RM
authors.lastname: Adam
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Krishnan
authors.affiliation: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048.
authors.forename: Beatrice S
authors.initials: BS
authors.lastname: Knudsen
authors.affiliation: 1] Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048 [2] Urological Diseases Research Center, Boston Children's Hospital, Boston, MA 02115 [3] Department of Surgery, Harvard Medical School, Boston, MA 02115.
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.affiliation: 1] Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048 [2] Urological Diseases Research Center, Boston Children's Hospital, Boston, MA 02115 [3] Department of Surgery, Harvard Medical School, Boston, MA 02115.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D034261:Epothilones / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D000080865:Formins; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008870:Microtubules / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C484571:DIAPH3 protein, human; D034261:Epothilones; D000080865:Formins; D043823:Taxoids; C093788:epothilone B