Gastrin-releasing peptide receptor as a prognostic biomarker and mediator of doxorubicin resistance in breast cancer

Resumo

Objective: This study aimed to verify the expression and prognostic implications of gastrin-releasing peptide receptor
(GRPR) in breast cancer by analyzing multiple cancer-related databases and complementary in vitro assays. Methods: GRPR
expression and its association with prognosis in breast cancer were assessed using different databases: OncoDB, Gent2,
and GEPIA. In vitro experiments were performed using MCF-7 and MDA-MB-231 breast cancer cell lines, both naïve and
treated with cytotoxic drugs. GRPR expression and cell viability were assessed to investigate potential roles in drug resistance. Results: Bioinformatics analysis revealed overexpression of GRPR in breast cancer compared to healthy tissue.
GRPR expression positively correlated with estrogen receptor and low-grade tumors (p<0.001). Among molecular subtypes, luminal A exhibited the highest levels of GRPR, followed by luminal B, human epidermal growth factor receptortype 2-positive (HER2+), triple-negative breast cancer (TNBC), and basal. Prognostic analysis using the Gent2 database
indicated that higher GRPR expression was associated with improved overall survival (p=0.004). However, GEPIA analysis did not confirm a statistically significant survival difference. In vitro, both cell lines treated with doxorubicin showed
decreased viability (p<0.0001), along with a significant increase in GRPR expression, with a fold change of 5.7 (p<0.0001)
for MCF-7 and 2.7 (p=0.007) for MDA-MB-231, suggesting that surviving cells express higher levels of GRPR. This pattern was not observed with cyclophosphamide, indicating a potential role of GRPR in acquired resistance to doxorubicin.
Conclusion: GRPR expression is associated with estrogen receptor positivity and may indicate a favorable prognosis in
breast cancer. Nonetheless, its upregulation following doxorubicin exposure suggests a potential role in chemoresistance.
The findings support GRPR as a promising biomarker for prognosis and a potential therapeutic target, particularly in the
context of resistance to anthracycline-based chemotherapy.