TY - JOUR
T1 - Piwi-interacting RNA 775 (piR-775) predicts favorable prognosis and regulates cell cycle and DNA damage response pathways in breast cancer
AU - Abohalawa, Bushra Yasin
AU - Eldous, Hend Ghassan
AU - Elango, Ramesh
AU - Vishnubalaji, Radhakrishnan
AU - Rashid, Sameera
AU - Ouararhni, Khalid
AU - Al Haj Zen, Ayman
AU - Alajez, Nehad M.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - Piwi-interacting RNAs (piRNAs) are small non-coding RNAs primarily recognized for their roles in germline development and genome stability. However, their contribution to breast cancer remains poorly understood. In this study, we profiled piRNA expression in 96 primary breast cancer tissues and explored the prognostic and functional significance of piR-775. Higher expression of piR-775 was significantly associated with improved relapse-free survival, suggesting its potential as a favorable prognostic biomarker. Functional assays in triple-negative breast cancer (TNBC) models demonstrated that piR-775 overexpression significantly suppressed colony formation and three-dimensional tumor growth. Using an organ-on-chip platform, piR-775 overexpression also inhibited TNBC cell migration and invasion. Transcriptomic analyses following piR-775 re-expression identified multiple downregulated target genes involved in cell cycle progression and DNA damage repair pathways, including POLE, BARD1, TPX2, BIRC5, and XRCC2, which were further validated by RT-qPCR. Integration with CRISPR screen data highlighted 47 essential piR-775 targets required for TNBC survival. Additionally, DNA damage assays indicated increased genomic instability upon piR-775 expression. Notably, combining piR-775 with the PARP inhibitor Olaparib led to enhanced cytotoxic effects, suggesting a synthetic lethal interaction. Furthermore, transcriptomic analysis of breast cancer revealed consistent downregulation of the PIWI proteins PIWIL2 and PIWIL4, indicating disruption of the piRNA–PIWI pathway in breast cancer. Collectively, these findings establish piR-775 as a tumor-suppressive piRNA with both prognostic and therapeutic relevance in breast cancer, particularly in TNBC. By impairing oncogenic signaling and enhancing the efficacy of PARP inhibitors, piR-775 emerges as a promising biomarker and a candidate for combination therapy.
AB - Piwi-interacting RNAs (piRNAs) are small non-coding RNAs primarily recognized for their roles in germline development and genome stability. However, their contribution to breast cancer remains poorly understood. In this study, we profiled piRNA expression in 96 primary breast cancer tissues and explored the prognostic and functional significance of piR-775. Higher expression of piR-775 was significantly associated with improved relapse-free survival, suggesting its potential as a favorable prognostic biomarker. Functional assays in triple-negative breast cancer (TNBC) models demonstrated that piR-775 overexpression significantly suppressed colony formation and three-dimensional tumor growth. Using an organ-on-chip platform, piR-775 overexpression also inhibited TNBC cell migration and invasion. Transcriptomic analyses following piR-775 re-expression identified multiple downregulated target genes involved in cell cycle progression and DNA damage repair pathways, including POLE, BARD1, TPX2, BIRC5, and XRCC2, which were further validated by RT-qPCR. Integration with CRISPR screen data highlighted 47 essential piR-775 targets required for TNBC survival. Additionally, DNA damage assays indicated increased genomic instability upon piR-775 expression. Notably, combining piR-775 with the PARP inhibitor Olaparib led to enhanced cytotoxic effects, suggesting a synthetic lethal interaction. Furthermore, transcriptomic analysis of breast cancer revealed consistent downregulation of the PIWI proteins PIWIL2 and PIWIL4, indicating disruption of the piRNA–PIWI pathway in breast cancer. Collectively, these findings establish piR-775 as a tumor-suppressive piRNA with both prognostic and therapeutic relevance in breast cancer, particularly in TNBC. By impairing oncogenic signaling and enhancing the efficacy of PARP inhibitors, piR-775 emerges as a promising biomarker and a candidate for combination therapy.
KW - Biomarkers
KW - Breast cancer
KW - Combination therapy
KW - DNA damage response
KW - Non-coding RNAs
KW - PiR-775
KW - PiRNAs
KW - Synthetic lethality
UR - https://www.scopus.com/pages/publications/105020864784
U2 - 10.1186/s40364-025-00856-1
DO - 10.1186/s40364-025-00856-1
M3 - Letter
C2 - 41189020
AN - SCOPUS:105020864784
SN - 2050-7771
VL - 13
JO - Biomarker Research
JF - Biomarker Research
IS - 1
M1 - 139
ER -