Dll1 quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.

TitleDll1 quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway.
Publication TypeJournal Article
Year of Publication2021
AuthorsKumar, 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
JournalNat Commun
Volume12
Issue1
Pagination432
Date Published2021/01/18
ISSN2041-1723
KeywordsAnimals, 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

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.

DOI10.1038/s41467-020-20664-5
Alternate JournalNat Commun
PubMed ID33462238
PubMed Central IDPMC7813834
Grant ListK22 CA193661 / CA / NCI NIH HHS / United States