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Resensitization of palbociclib-resistant MCF-7 cells by inhibiting TGF-beta-induced epithelial-mesenchymal transition

Authors
Chang, MinsunPark, SujeongHa An, Byung
Issue Date
May-2020
Publisher
American Society of Clinical Oncology
Citation
JOURNAL OF CLINICAL ONCOLOGY, v.38, no.15-suppl.
Journal Title
JOURNAL OF CLINICAL ONCOLOGY
Volume
38
Number
15-suppl.
URI
https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/17736
DOI
10.1200/JCO.2020.38.15_suppl.e13061
ISSN
0732-183X
Abstract
Background: Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is the most recent therapeutic method to treat estrogen receptor (ER)-positive breast cancer. Three CDK4/6 inhibitors have been approved by the FDA. The acquired resistance to CDK4/6 inhibitors are expected to have a negative impact on success of breast cancer therapy. It is critical to understand the molecular mechanisms underlying drug resistances to devise a better regimen or overcome drug resistance. Methods: The derivative MCF-7 (MCF-7:PR) cells which exert acquired resistance to palbociclib (PCB), one of the FDA-approved CDK4/6 inhibitors, are recently established. The EMT characteristics, major mechanisms for the EMT, and inhibition of TGF-β signaling pathways are studied in MCF-7:PR cells. Results: The mesenchymal markers are increased and the epithelial ones are decreased at both mRNA and protein levels in our cell line model. Transwell migration and would healing assays also demonstrated that MCF-7:PR cells exert EMT properties. Hyperactivation of TGF-β/Smad signaling was observed in MCF-7:PR cells. Chemical inhibition of TGF-β signaling lead to diminished cell migration and resistance to PCB. Conclusions: Resistance to PCB in MCF-7 cells resulted in significant changes in cell motility and molecular markers associated with EMT. In particular, TGF-β signaling is closely related to EMT and its inhibition reversed the EMT and cellular response to PCT. Our findings suggest that the modulation of EMT via inhibition of TGF-β signaling can be one of strategies to bypass PCB resistance in ER-positive breast cancer.
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