Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling

• Published in: International journal of molecular sciences Vol. 22; no. 22; p. 12438
• Main Authors: Paramanantham, Anjugam, Jung, Eun-Joo, Kim, Hye-Jung, Jeong, Bae-Kwon, Jung, Jin-Myung, Kim, Gon-Sup, Chan, Hong-Soon, Lee, Won-Sup
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.11.2021; MDPI
• Subjects: AKT protein; Antibiotics, Antineoplastic - pharmacology; Antigens, CD - genetics; Antigens, CD - metabolism; Autocrine Communication - drug effects; Autocrine Communication - genetics; Autocrine signalling; beta Catenin - genetics; beta Catenin - metabolism; Breast cancer; Cadherins - genetics; Cadherins - metabolism; Cancer therapies; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; CSCs; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Dormancy; Doxorubicin; Doxorubicin - pharmacology; doxorubicin-resistant; Drug resistance; Drug Resistance, Neoplasm - genetics; E-cadherin; EGFR; Epidermal growth factor receptors; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Gelatinase A; Gelatinase B; Gene Expression Regulation, Neoplastic; Genotype & phenotype; Giant cells; Humans; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Invasiveness; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; MDA-MB-231; Mesenchyme; Metastasis; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular modelling; Morphology; N-Cadherin; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phenotypes; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Stem cells; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; β-Catenin; breast cancer; doxorubicin-resistant; EGFR; MDA-MB-231; CSCs
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222212438

Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial-mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with maintaining resistance to doxorubicin, or whether the phenotypes can be transferred to other doxorubicin-sensitive cells. Here, we characterized the phenotype of doxorubicin-resistant TNBC cells while monitoring the EMT process and expansion of CSCs during the establishment of doxorubicin-resistant MDA-MB-231 human breast cancer cells (DRM cells). In addition, we assessed the potential signaling associated with the EMT process and expansion of CSCs in doxorubicin-resistance of DRM cells. DRM cells exhibited morphological changes from spindle-shaped MDA-MB-231 cells into round-shaped giant cells. They exhibited highly proliferative, EMT, adhesive, and invasive phenotypes. Molecularly, they showed up-regulation of Cyclin D1, mesenchymal markers (β-catenin, and N-cadherin), MMP-2, MMP-9, ICAM-1 and down-regulation of E-cadherin. As the molecular mechanisms responsible for the resistance to doxorubicin, up-regulation of EGFR and its downstream signaling, were suggested. AKT and ERK1/2 expression were also increased in DRM cells with the advancement of resistance to doxorubicin. Furthermore, doxorubicin resistance of DRM cells can be transferred by autocrine signaling. In conclusion, DRM cells harbored EMT features with CSC properties possessing increased proliferation, invasion, migration, and adhesion ability. The doxorubicin resistance, and doxorubicin-induced EMT and CSC properties of DRM cells, can be transferred to parental cells through autocrine signaling. Lastly, this feature of DRM cells might be associated with the up-regulation of EGFR.