Title:Transcriptome Profiling of Cisplatin Resistance in Triple-negative
Breast Cancer: New Insight into the Role of PI3k/Akt Pathway
Volume: 23
Issue: 6
关键词:
顺铂，乳腺癌，耐药性，TNBC，PI3k / Akt，RNA-seq。
摘要:
Background: Aggressive nature of triple negative breast cancer (TNBC) is
associated with poor prognosis compared with other breast cancer types. Current
guidelines recommend the use of Cisplatin for the management of TNBC. However, the
development of resistance to cisplatin is the primary cause of chemotherapy failure.
Objective: In the present study, we aimed to develop a stable cisplatin-resistant TNBC
cell line to investigate the key pathways and genes involved in cisplatin-resistant TNBC.
Methods: The MDA-MB-231 cell was exposed to different concentrations of cisplatin.
After 33 generations, cells showed a resistant phenotype. Then, RNA-sequencing
analysis was performed in cisplatin-resistant and parent cell lines. The RNA-sequencing
data was verified by quantitative PCR (qPCR).
Results: The IC50 of the resistant cell increased to 10-fold of a parental cell (p<0.001).
Also, cisplatin-resistant cells show cross-resistance to other drugs, including 5-
fluorouracil, paclitaxel, and doxorubicin. Resistant cells demonstrated reduced drug
accumulation compared to the parental cells. Results showed there were 116
differentially expression genes (DEGs) (p<0.01). Gene ontology analysis revealed that
the DEGs have several molecular functions, including binding and transporter activity.
Functional annotation showed that the DEGs were enriched in the drug resistancerelated
pathways, especially the PI3K-Akt signaling pathway. The most important genes
identified in the protein-protein interaction network were heme oxygenase 1 (HMOX1)
and TIMP metallopeptidase inhibitor 3 (TIMP3).
Conclusion: We have identified several pathways and DEGs associated with the PI3KAkt
pathway, which provides new insights into the mechanism of cisplatin resistance,
and potential drug targets in TNBC.
