title: Induction of CXCR2 ligands, stem cell-like phenotype, and metastasis in chemotherapy-resistant breast cancer cells.
abstract: CXCR2 and its ligands have been shown to play an important role in tumor angiogenesis, therapy resistance and progression. In this study, we investigated whether CXCR2 ligands are responsible for the survival advantage and metastasis of drug-resistant cells and examined the underlying mechanism(s) doxorubicin or paclitaxel resistant mammary tumor cells. Our results demonstrated that drug-resistant Cl66 cells upregulated CXCR2 ligands but downregulated expression of CXCR2. We observed delayed tumor growth but increased metastasis in mice using these drug-resistant cells. Furthermore, we observed differential upregulation of stem cell and mesenchymal markers in the doxorubicin and paclitaxel-resistant tumor cells. Abrogation of the CXCR2 signaling axis using CXCR2 ligand neutralization resulted in significant inhibition of drug-resistant cell growth. Together, our data suggest chemotherapy-specific differential regulation of CXCR2 ligands, stem cell-like and mesenchymal phenotypes, and enhanced metastasis in drug-resistant cells and targeting CXCR2 signaling, may help circumvent therapy resistance in breast cancer.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI.
authors.forename: Bhawna
authors.initials: B
authors.lastname: Sharma
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Varney
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Sugandha
authors.initials: S
authors.lastname: Saxena
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE; Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE. Electronic address: rsingh@unmc.edu.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008024:Ligands; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D023063:Receptors, Interleukin-8B; D004317:Doxorubicin; D017239:Paclitaxel
keywords: CXCR2; Chemokines; Stem cell; Therapy resistance