Clinical Significance of Hepatitis A Virus Cellular Receptor 1 (HAVCR-1) in Breast Cancer

Abstract

<title>Abstract</title> <bold>Background:</bold> Hepatitis A virus cellular receptor 1 (HAVCR-1), first discovered as the entry factor for hepatitis A virus, has since been recognized as a tumor-associated antigen and is currently being intensively explored as a prognostic biomarker across multiple malignancies, including gastric and colorectal cancers. However, its contribution to breast cancer remains ambiguous. This study investigated the expression and clinical significance of HAVCR-1 in breast cancer. <bold>Methods:</bold> HAVCR-1 expression was evaluated via quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in a cohort of fresh-frozen normal and breast cancer tissues. Expression levels were correlated with clinicopathological parameters, including the Nottingham prognostic index, tumor stage, histological subtype, hormone receptor status (ER, PR, HER2), and survival outcomes. The prognostic and predictive value of HAVCR-1 was assessed via chi-square tests and receiver operating characteristic (ROC) analysis. The median follow-up period was 120 months. In vitro, HAVCR-1 was knocked down via siRNA in the MCF-7 and MDA-MB-231 cell lines, and the response to docetaxel was evaluated on the basis of the IC50 values. Additionally, ROC plotter analysis was used to assess the association between HAVCR-1 expression and therapeutic response in breast cancer patients. <bold>Results:</bold> Although qPCR revealed no statistically significant difference in HAVCR-1 mRNA levels between tumor and normal tissues (P=0.2697), IHC revealed increased protein expression in breast cancer tissues. Low HAVCR-1 expression was significantly associated with improved overall survival (OS, P &lt; 0.01) and relapse-free survival (RFS, P=0.04). Subgroup analysis indicated that the survival benefit of low HAVCR-1 expression was particularly evident in ER-positive (P=0.046) and HER2-positive (P=0.004) subtypes but not in triple-negative breast cancer (TNBC). In vitro knockdown of HAVCR-1 conferred resistance to docetaxel in both MCF-7 (IC50: 0.86 nM vs. 1.75 nM) and MDA-MB-231 (IC50: 1.35 nM vs. 15.48 nM) cells. Clinically, patients with high HAVCR-1 expression are more likely to exhibit resistance to chemotherapy, particularly those with the luminal A, luminal B, and TNBC subtypes, but not those with HER2+/ER− tumors. <bold>Conclusion:</bold> HAVCR-1 is an independent prognostic factor for OS and RFS in breast cancer patients and may serve as a predictive biomarker for chemotherapy response. Its combination with ER, PR, and HER2 status could enhance prognostic stratification and therapeutic decision-making.

Affiliated Institutions

• Shandong First Medical University CN
• Cardiff University GB
• Shandong Tumor Hospital CN
• Tianjin Medical University Cancer Institute and Hospital CN
• Academy of Medical Sciences GB

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