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Principal Investigator: Runhua Runa Liu
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2019
Award: $204,188
Funding agency: National Cancer Institute
Project Summary
Background: Triple-negative (estrogen receptor [ER]/progesterone receptor [PR]/human epidermal growth
factor receptor 2 [HER2]-negative) breast cancer (TNBC) is a highly aggressive subtype of breast cancer.
Approximately 34% of patients with TNBC will experience distant recurrence within 3 years and eventually
develop chemotherapy-resistant, incurable disease. Therefore, development of novel treatments is necessary.
Accumulating data demonstrate that microRNA (miR)-146a, which is part of the miR-146 family, inhibits cancer
cell proliferation, invasion, and metastasis in human cancers, including TNBC, suggesting that miR-146a
functions as a tumor suppressor in tumor cells. Previously, our group demonstrated that miR-146a negatively
regulates NF-κB activation to inhibit tumor growth in TNBC. Furthermore, our data suggested that miR-146a
suppresses TNBC colonization through the cellular transfer of miR-146a by exosomes at distant sites and the
delivery of miR-146a mimic influences the cells at metastatic sites in vivo. Thus, miR-146a may have potential
to block TNBC cell colonization at distant sites. We now seek to test the therapeutic value of miR-146a in the
prevention or treatment of TNBC metastasis.
Hypothesis: We hypothesize that miR-146a effectively blocks the tumor colonization of disseminated TNBC
cells at metastatic sites. This hypothesis will be tested in two specific aims: 1) To evaluate the therapeutic value
of miR-146a in blocking tumor colonization at metastatic sites, and 2) To determine the mechanism of miR-146a-
mediated suppression of tumor metastasis.
Approach: First, to address the impact of miR-146a on preventing human TNBC cell colonization, we will
intravenously inject scramble miR or miR-146a mimic nanoparticles once circulating tumor cells are detected in
xenograft mouse models. Next, to evaluate the efficacy of miR-146a in inhibiting tumor metastasis in a clinically
relevant model, we will intravenously inject scramble miR or miR-146a mimic nanoparticles into TNBC patient-
derived xenograft mouse models and determine if miR-146a blocks TNBC metastasis to distant organs. Finally,
to identify which cells are influenced by miR-146a and which miR-146a-regulated pathways are involved in tumor
metastasis, we will use our innovative transgenic mouse model that expresses a miR-146a-targeted GFP
reporter to monitor miR-146a activity in specific cell types during tumor metastasis.
Innovation and Significance: TNBC remains a highly aggressive and fatal subtype of breast cancer, with the
highest mortality in young minority women. Developing effective therapies to treat this disease is crucial. The
data from this study will not only provide a novel therapeutic approach to block tumor metastasis in TNBC, but
will also identify a new molecular mechanism responsible for tumor metastasis. Since our preliminary studies
support the suppressive role of miR-146a in tumor metastasis, the tight focus of this project will allow us to
establish the mechanism-driven innovative pre-clinical studies that could lead to a first-in-human clinical trial.
Terms: <4T1><Address><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Antibodies><Bone Marrow><Bone Marrow Reticuloendothelial System><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><CXC-R4><CXCR-4><CXCR4><CXCR4 gene><Cancer Relapse><Cancers><Cause of Death><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cells><Cellular Proliferation><Clinical><Clinical Trials><D2S201E><Data><Development><Disease><Disorder><Distant><Down-Regulation><Downregulation><EGF Receptor><EGFR><ERBB Protein><Endocrine Gland Secretion><Endocrine Therapy><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Estrogen Receptors><FB22><FOXP3><FOXP3 gene><Family><Fats><Fatty acid glycerol esters><Female><Femara><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Forkhead Box P3><Genes><Goals><HER1><HER2 Monoclonal Antibody><HM89><HSY3RR><Herceptin><Heterograft><Heterologous Transplantation><Histologic><Histologically><Hormonal Therapy><Hormones><Human><IRAK><IRAK1><IRAK1 gene><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunofluorescence><Immunofluorescence Immunologic><Immunosuppressed Host><Interleukin-1 Receptor-Associated Kinase 1><Intravenous><JM2><LAP3><LCR1><LESTR><Label><Lead><Letrozole><Luciferase Immunologic><Luciferases><MDA MB 231><MDA-231><MDA-MB-468><MDA-MB231><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Mammary gland><Mediating><Metastasis><Metastasis to Lymph Nodes><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to Lymph Nodes><Metastatic Tumor><Metastatic Tumor to Lymph Nodes><Mice><Mice Mammals><Micro RNA><MicroRNAs><Minority><MoAb HER2><Modeling><Modern Man><Molecular><Molecular Marker of Prognosis><Molecular Tumor Suppression><Monitor><Murine><Mus><NPY3R><NPYR><NPYRL><NPYY3R><Nature><Neoplasm Circulating Cells><Neoplasm Metastasis><Operative Procedures><Operative Surgical Procedures><Organ><Pathway interactions><Patients><Pb element><Prevention><Primary Neoplasm><Primary Tumor><Progesterone Receptors><Progestin Receptors><Prognosis Marker><Prognostic Marker><Progression-Free Survivals><Radiation><Recurrence><Recurrent><Relapse><Reporter><Resistance><Role><SCURFIN><Secondary Neoplasm><Secondary Tumor><Site><Surgical><Surgical Interventions><Surgical Procedure><TGF-alpha Receptor><TNBC><TNF Receptor-Associated Factor 6 Gene><TRAF6><TRAF6 gene><Tamoxifen><Testing><Therapeutic><Therapeutic Hormone><Time><Transforming Growth Factor alpha Receptor><Transgenic Mice><Trastuzumab><Tumor Cell><Tumor Suppression><Tumor Suppressor Proteins><Tumor-Derived><Urogastrone Receptor><Woman><Work><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><base><breast tumor cell><c-erb-2 Monoclonal Antibody><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer metastasis><cancer microenvironment><cell type><chemotherapy><circulating neoplastic cell><circulating tumor cell><clinical relevance><clinically relevant><developmental><effective therapy><effective treatment><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><exosome><experience><first in man><first-in-human><flow cytophotometry><heavy metal Pb><heavy metal lead><hormone receptor-positive><hormone therapy><immunosuppressed patient><improved><in vivo><innovate><innovation><innovative><intravenous injection><lipid nanoparticle><lymph node metastasis><malignancy><malignant breast neoplasm><malignant breast tumor><mammary><mammary tumor><metastasis prevention><miRNA><miRNAs><mortality><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><neoplastic cell><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic target><novel therapy approach><novel therapy target><pathway><pelle><peripheral blood><pre-clinical study><preclinical study><prevent><preventing><prognostic biomarker><prognostic indicator><proto-oncogene protein c-erbB-1><rapid growth><resistant><rhuMAb HER2><social role><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic evaluation><therapeutic testing><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumor suppressor><tumor xenograft><xeno-transplant><xeno-transplantation>