Abstract
Development of chemoresistance in breast cancer patients greatly increases mortality. Thus, understanding mechanisms underlying breast cancer resistance to chemotherapy is of paramount importance to overcome this clinical challenge. Although activated Notch receptors have been associated with chemoresistance in cancer, the specific Notch ligands and their molecular mechanisms leading to chemoresistance in breast cancer remain elusive. Using conditional knockout and reporter mouse models, we demonstrate that tumor cells expressing the Notch ligand Dll1 is important for tumor growth and metastasis and bear similarities to tumor-initiating cancer cells (TICs) in breast cancer. RNA-seq and ATAC-seq using reporter models and patient data demonstrated that NF-κB activation is downstream of Dll1 and is associated with a chemoresistant phenotype. Finally, pharmacological blocking of Dll1 or NF-κB pathway completely sensitizes Dll1+ tumors to chemotherapy, highlighting therapeutic avenues for chemotherapy resistant breast cancer patients in the near future.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Benzamides / pharmacology
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Benzamides / therapeutic use
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Breast / pathology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Calcium-Binding Proteins / antagonists & inhibitors
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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Datasets as Topic
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Disease Models, Animal
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Doxorubicin / pharmacology
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Doxorubicin / therapeutic use
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics*
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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NF-kappa B p50 Subunit / antagonists & inhibitors
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NF-kappa B p50 Subunit / metabolism*
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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RNA-Seq
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Receptors, Notch / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
Substances
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Benzamides
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Calcium-Binding Proteins
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DLK1 protein, human
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Dlk1 protein, mouse
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Membrane Proteins
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NF-kappa B p50 Subunit
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NFKB1 protein, human
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Receptors, Notch
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Nfkb1 protein, mouse
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N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide
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Doxorubicin