Title | Dll1 quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Kumar, S, Nandi, A, Singh, S, Regulapati, R, Li, N, Tobias, JW, Siebel, CW, Blanco, MAndres, Klein-Szanto, AJ, Lengner, C, Welm, AL, Kang, Y, Chakrabarti, R |
Journal | Nat Commun |
Volume | 12 |
Issue | 1 |
Pagination | 432 |
Date Published | 2021 Jan 18 |
ISSN | 2041-1723 |
Keywords | Animals, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Breast, Breast Neoplasms, Calcium-Binding Proteins, Cell Line, Tumor, Cell Proliferation, Cell Survival, Datasets as Topic, Disease Models, Animal, Doxorubicin, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Membrane Proteins, Mice, Mice, Knockout, Neoplastic Stem Cells, NF-kappa B p50 Subunit, Receptors, Notch, RNA-Seq, Signal Transduction |
Abstract | <p>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.</p> |
DOI | 10.1038/s41467-020-20664-5 |
Alternate Journal | Nat Commun |
PubMed ID | 33462238 |
PubMed Central ID | PMC7813834 |
Grant List | K22 CA193661 / CA / NCI NIH HHS / United States |