title: Combining miR-10b-Targeted Nanotherapy with Low-Dose Doxorubicin Elicits Durable Regressions of Metastatic Breast Cancer.
abstract: The therapeutic promise of microRNA (miRNA) in cancer has yet to be realized. In this study, we identified and therapeutically exploited a new role for miR-10b at the metastatic site, which links its overexpression to tumor cell viability and proliferation. In the protocol developed, we combined a miR-10b-inhibitory nanodrug with low-dose anthracycline to achieve complete durable regressions of metastatic disease in a murine model of metastatic breast cancer. Mechanistic investigations suggested a potent antiproliferative, proapoptotic effect of the nanodrug in the metastatic cells, potentiated by a cell-cycle arrest produced by administration of the low-dose anthracycline. miR-10b was overexpressed specifically in cells with high metastatic potential, suggesting a role for this miRNA as a metastasis-specific therapeutic target. Taken together, our results implied the existence of pathways that regulate the viability and proliferation of tumor cells only after they have acquired the ability to grow at distant metastatic sites. As illustrated by miR-10b targeting, such metastasis-dependent apoptotic pathways would offer attractive targets for further therapeutic exploration.
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Byunghee
authors.initials: B
authors.lastname: Yoo
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Amol
authors.initials: A
authors.lastname: Kavishwar
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Alana
authors.initials: A
authors.lastname: Ross
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Doris P
authors.initials: DP
authors.lastname: Tabassum
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Natalia
authors.initials: N
authors.lastname: Barteneva
authors.affiliation: Molecular Medicine Core, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Victoria
authors.initials: V
authors.lastname: Petkova
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Pamela
authors.initials: P
authors.lastname: Pantazopoulos
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Aseda
authors.initials: A
authors.lastname: Tena
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. zmedarova@partners.org amoore@helix.mgh.harvard.edu.
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.affiliation: Molecular Imaging Laboratory, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. zmedarova@partners.org amoore@helix.mgh.harvard.edu.
authors.forename: Zdravka
authors.initials: Z
authors.lastname: Medarova
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage*; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D053758:Nanoparticles; D009362:Neoplasm Metastasis; D010641:Phenotype; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C547183:MIRN10 microRNA, human; D035683:MicroRNAs; D004317:Doxorubicin