title: The class I HDAC inhibitor Romidepsin targets inflammatory breast cancer tumor emboli and synergizes with paclitaxel to inhibit metastasis.
abstract: Inflammatory breast cancer (IBC) is the most metastatic variant of locally advanced breast cancer. IBC has distinctive characteristics including invasion of tumor emboli into the skin and rapid disease progression. Given our previous studies suggesting that HDAC inhibitors have promise in targeting IBC, the present study revealed that the class I HDAC inhibitor Romidepsin (FK-288, Istodax; Celgene Corporation, Summit, NJ) potently induced destruction of IBC tumor emboli and lymphatic vascular architecture. associated with inhibition of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha, (HIF1alpha) proteins in the Mary-X pre-clinical model of IBC. Romidepsin treatment induced clinically relevant biomarkers in including induction of acetylated Histone 3 (Ac-H3) proteins, apoptosis, and increased p21WAF1/CIP1. Romidepsin, alone and synergistically when combined with Paclitaxel, effectively eliminated both primary tumors and metastatic lesions at multiple sites formed by the SUM149 IBC cell line. This is the first report of the ability of an HDAC inhibitor to eradicate IBC tumor emboli, to destroy the integrity of lymphatic vessel architecture and to target metastasis. Furthermore, Romidepsin, in combination with a taxane, warrants evaluation as a therapeutic strategy that may effectively target the skin involvement and rapid metastasis that are hallmarks of IBC.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. frobertson@mdanderson.org
authors.forename: Fredika M
authors.initials: FM
authors.lastname: Robertson
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Khoi
authors.initials: K
authors.lastname: Chu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Boley
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Moishia C
authors.initials: MC
authors.lastname: Wright
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Moraes
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Green
authors.affiliation: The Department of Pathology, The University of Nevada School of Medicine, Reno NV, USA.
authors.forename: Sanford H
authors.initials: SH
authors.lastname: Barsky
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.affiliation: Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D017239:Paclitaxel / Q000008:administration & dosage*; D018874:Spheroids, Cellular; D023041:Xenograft Model Antitumor Assays
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; D017239:Paclitaxel