Prognostic Significance of Circular HER2 and Its Association with EMT Markers in Advanced Breast Cancer

Nesma A. Ghazal; Hanan Mohamed Nomeir; Fawziya A. R Ibrahim; Shaymaa Ali Elhamshary; Ola A. Sakr; Aisha A. Essam Eldin; O. Al-Masry

doi:10.31557/APJCB.2026.11.4.1085

Authors

Nesma A. Ghazal Biochemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Hanan Mohamed Nomeir Medical Biochemistry Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
Fawziya A. R Ibrahim Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Shaymaa Ali Elhamshary Biochemistry Department, Faculty of Sciences, Alexandria University, Alexandria, Egypt.
Ola A. Sakr Cancer Management and Research Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Aisha A. Essam Eldin 6Pathology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
O. Al-Masry Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.

DOI:

https://doi.org/10.31557/APJCB.2026.11.4.1085

Keywords:

Metastatic TNBC, Circ-HER2, EMT markers, Twist1, ILE2

Abstract

Introduction: Globally, breast cancer (BC) represents the most prevalent malignancy among females. In the field of epigenetic regulation, non-coding circular RNAs have recently been identified as key contributors to BC pathogenesis. Among this class, circular HER2 (Circ-HER2 ) has been documented to be overexpressed in various cancers, including BC. Particularly, in triple-negative breast cancer (TNBC), elevated Circ-HER2 expression correlates with increased metastatic potential, invasiveness, and cell proliferative capacity. Nevertheless, the precise molecular mechanisms through which Circ-HER2 is implicated in TNBC remains inadequately understood and further investigations are still needed. Consequently, this study aimed to investigate the Circ-HER2 gene expression profile in a sample of BC patients and to elucidate its association with other prognostic biomarkers and disease aggressiveness phenotypes.

Patients and Methods: This study was conducted on 40 breast cancer patients, two tissue specimens were collected from each patient: one from the malignant tumor (MT) and the other sample from the corresponding adjacent, microscopically normal breast tissue (TAN). q-RT-PCR was employed for gene expression profiling of Circ-HER2, E-Cadherin, ILE2, and Twist1 in malignant as well as normal tissues.

Results: Our results revealed a significant upregulation of Circ-HER2, ILE2, and Twist1 in malignant tissues compared to the matched adjacent normal tissues. Furthermore, Circ-HER2 expression demonstrated a statistically significant correlation with E-Cadherin expression, ILE2, and Twist1. However, when the TNBC patients analyzed separately, Circ-HER2 was significantly higher than E-Cadherin, while its expression was not significantly different than the other metastatic markers.

Conclusion: In conclusion, the significant Circ-HER2 overexpression in breast cancer tissues, along with significant correlation of Circ-HER2 with increased levels of key EMT biomarkers, especially in TNBC patients, suggest a potential role for Circ-HER2 in promoting an aggressive, pro-metastatic phenotype in breast cancer. These findings provide preliminary clinical evidence supporting the oncogenic function of Circ-HER2 and underscore the need for further mechanistic investigations to delineate its precise molecular pathway and validate its potential as a prognostic biomarker or therapeutic target in breast cancer, particularly in the aggressive subtypes such as TNBC, where therapeutic options are limited.