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Kumar S , Nandi A , Singh S , Regulapati R , Li N , Tobias JW , Siebel CW , Blanco MA , Klein-Szanto AJ , Lengner C , Welm AL , Kang Y , Chakrabarti R
Dll1(+) quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway
Nat Commun. 2021 Jan 18;12(1) :432
PMID: 33462238    PMCID: PMC7813834   
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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.
2041-1723 Kumar, Sushil Orcid: 0000-0003-0547-745x Nandi, Ajeya Singh, Snahlata Regulapati, Rohan Orcid: 0000-0002-4906-7092 Li, Ning Orcid: 0000-0001-5997-5556 Tobias, John W Siebel, Christian W Blanco, Mario Andres Klein-Szanto, Andres J Lengner, Christopher Orcid: 0000-0002-0574-5189 Welm, Alana L Orcid: 0000-0002-1412-1351 Kang, Yibin Orcid: 0000-0002-1626-6730 Chakrabarti, Rumela K22 CA193661/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Commun. 2021 Jan 18;12(1):432. doi: 10.1038/s41467-020-20664-5.