Document text
Principal Investigator: Jun He
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2024
Award: $264,296
Funding agency: National Cancer Institute
Breast cancer (BCa) is the leading cause of women cancer mortality worldwide, and triple negative breast
cancer (TNBC) cells accounts for 15-20% BCa. However, higher therapeutic resistance and lower survival
of TNBC patients remain the major hinder of BCa treatment. Doxorubicin (Dox) and radiation are commonly
used for TNBC treatment. In our preliminary study, we found that TNBC showed much lower expression
levels of miR-152. Higher expression levels of zeste homologue 2 (EZH2) and DNA hypermethylation were
involved in miR-152 suppression in TNBC cells. To understand mechanism of miR-152 suppression, and
role and mechanism of miR-152 in regulating cancer development and Dox- and radiation-induced
resistance, we performed a lot of preliminary experiments to identify what molecules that were potential
miR-152 direct targets as well as that were upregulated in Dox-resistant TNBC or PDX tumor tissues. We
found that pyruvate kinase muscle 2 (PKM2), solute Carrier Family 7 Member 5 (SLC7A5), and
polypyrimidine tract-binding protein (PTBP1) as direct targets of miR-152 with potential ability to converse
Dox-mediated resistance. PKM2, SLC7A5 and PTBP1 levels were increased when miR-152 expression
was suppressed in TNBC cells and PDX model. We found that miR-152 suppression played an important
role in mediating TNBC metabolic reprogramming, Warburg effect switch, tumor growth and Dox resistance
through PKM2/SLC7A5/PTBP1. We showed that overexpression of miR-152 or PKM2 knockdown rendered
TNBC cells more sensitive to radiation treatment. These new findings create new opportunity to investigate
mechanism of TNBC therapeutic resistance. We hypothesize that resistance to chemotherapy and
radiation treatment, metabolic reprogramming, and TNBC development are induced by miR-152
suppression and upregulation of PKM2, SLC7A5, and PTBP1. To test this central hypothesis, we will
perform experiments through three aims. In Aim 1, we will investigate role and mechanism of miR-152
suppression in TNBC cells in doxorubicin- and radiation-induced resistance; and role and mechanism of
PKM2 switch and induction via alternative splicing by miR-152 suppression to induce Warburg effect,
therapeutic resistance, and tumor growth. In Aim 2, we will determine role and mechanism of miR-
152/SLC7A5/PTBP1 pathway in regulating metabolic reprogramming and Warburg effect switch, and in
mediating doxorubicin- and radiation-induced therapeutic resistance. In Aim 3, we will determine whether
miR-152 suppression and PKM2 induction regulate tumor angiogenesis through CXCL8 expression using a
humanized chimeric tumor model; and whether levels of miR-152, PKM2, HIF-1α, hnRNPA3, SLC7A5, and
PTBP1 are correlated each other, and are correlated with therapeutic responses and with the cancer stages
and survival. This R01 project will identify mechanisms of therapeutic resistance, and metabolic
reprogramming; and provide information for developing new treatment option of TNBC in the future.
Terms: <14-Hydroxydaunomycin><3-10C><AMCF-I><ATP-protein phosphotransferase><Adriamycine><Affect><Alternate Splicing><Alternative RNA Splicing><Alternative Splicing><Amino Acids><Animal Model><Animal Models and Related Studies><Biology><Body Tissues><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Cancer Treatment><Breast Tumor Patient><CXCL8><Cancer Treatment><Cancers><Cell Body><Cell Line><Cell model><CellLine><Cells><Cellular model><Chemotherapy and Radiation><Chemotherapy and/or radiation><D10S102><DNA><DNA Methylation><Data><Deoxyribonucleic Acid><Development><Doxorubicin><Doxorubicina><ER Positive><ER+><Endothelial Cells><Estrogen receptor positive><FBRNP><Family><Future><GCP1><GeneHomolog><Goals><HNRPA3><HNRPA3 gene><Heterogeneous-Nuclear Ribonucleoproteins><Homolog><Homologous Gene><Homologue><Human><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Hypermethylation><IL-8><IL8><IL8 gene><Informofer><Isoforms><K60><Kinase Family Gene><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Metabolic><Methylation><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular><Muscle><Muscle Tissue><PDX model><PTB Protein><PTB Splicing Factor><Pathway interactions><Patient derived xenograft><Play><Polypyrimidine Tract-Binding Protein><Promoter Regions><Promotor Regions><Protein Isoforms><Protein Kinase><Proteins><Pyruvate Kinase><R-Series Research Projects><R01 Mechanism><R01 Program><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Receptor Protein><Research Grants><Research Project Grants><Research Projects><Resistance><Role><SCYB8><Signal Pathway><Strains Cell Lines><TNBC><TSG-1><Testing><Therapeutic><Therapeutic procedure><Tissues><Tumor Angiogenesis><Tumor Tissue><Up-Regulation><Upregulation><Warburg Effect><Woman><aminoacid><angiogenesis><anti-cancer therapy><b-ENAP><breast tumor cell><cancer cell><cancer cell metabolism><cancer metabolism><cancer survival><cancer therapy><cancer-directed therapy><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><cohort><cultured cell line><developmental><experiment><experimental research><experimental study><experiments><genetic promoter element><genetic promoter sequence><glycogen synthase a kinase><hnRNP><hnRNPA3><hydroxyalkyl protein kinase><improved><knock-down><knockdown><malignancy><malignant breast tumor><member><miRNA><miRNAs><model of animal><mortality><multidisciplinary><muscular><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><orthotopic breast adenocarcinoma><orthotopic breast cancer><orthotopic breast carcinoma><orthotopic breast tumor><overexpress><overexpression><p57 Cytoplasmic RNA-Binding Protein><pPTB><paracrine><pathway><patient derived xenograft model><phosphoenol transphosphorylase><phosphoenolpyruvate kinase><phosphorylase b kinase kinase><promoter sequence><radiation or chemotherapy><radiation treatment><receptor><resistance to therapy><resistant><resistant to therapy><response to therapy><response to treatment><social role><solute><therapeutic resistance><therapeutic response><therapy resistant><therapy response><translational opportunities><translational potential><treatment resistance><treatment response><treatment responsiveness><treatment with radiation><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metabolism><tumor growth><tumor metabolism>