HDAC inhibitors target IRS4 to enhance antiAR therapy in ARpositive triplenegative breast cancer.
Int J Oncol
; 64(3)2024 03.
Article
in En
| MEDLINE
| ID: mdl-38214343
ABSTRACT
Triplenegative breast cancer (TNBC) is the most malignant subtype of breast cancer. Androgen receptor (AR) has been identified as a potential therapeutic target for ARpositive TNBC; however, clinical trials have not yet produced an effective treatment. The present study aimed to identify a novel treatment regimen to improve the prognosis of ARpositive TNBC. First, a combination of an AR inhibitor (enzalutamide, Enz) and a selective histone deacetylase inhibitor (chidamide, Chid) was used to treat ARpositive TNBC cell lines, and a synergistic effect of these drugs was observed. The combination treatment inhibited cell proliferation and migration by arresting the cell cycle at the G2/M phase. Subsequently, nextgeneration sequencing was performed to detect changes in gene regulation. The results showed that the PI3K/Akt signalling pathway was significantly inhibited by the combination treatment of Enz and Chid. Gene Set Enrichment Analysis revealed that the combination group was significantly enriched in KRAS signalling. Analysis of the associated genes revealed that insulin receptor substrate 4 (IRS4) may have a critical role in blocking the activation of KRAS signalling. In a mouse xenograft model, combination treatment also inhibited the PI3K/Akt signalling pathway by upregulating the expression of IRS4 and thereby suppressing tumour growth. In conclusion, the results of the present study revealed that combination treatment with Enz and Chid can upregulate IRS4, which results in the blocking of KRAS signalling and suppression of tumour growth. It may be hypothesised that the expression levels of IRS4 could be used as a biomarker for screening patients with ARpositive TNBC using Enz and Chid combination therapy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Histone Deacetylase Inhibitors
/
Triple Negative Breast Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Int J Oncol
Year:
2024
Document type:
Article