DOI: 10.1177/10732748261469370 ISSN: 1073-2748
Clinical Significance of SOX2 Promoter Methylation in Breast Cancer Prognosis
Farhan Maqbool, Alfar Ahamed, Summaya Anwar, Muqadas Fatima, Shane Zahra, Erum Najeeb, Muhammad Saeed
Introduction
SOX2
, a key pluripotency gene, plays a central role in breast cancer stem cell (BCSC) biology, driving tumor aggressiveness. Although
SOX2
dysregulation has been widely studied across various cancers, its specific regulatory mechanisms in breast cancer (BC) remain incompletely elucidated. This study examined the regulatory axis of the
SOX2
gene and associated molecular mechanisms underlying BCSC maintenance and prognosis.
Methods
This retrospective cross-sectional study analyzed breast tumor tissues and adjacent normal controls collected consecutively from two tertiary hospitals.
SOX2
promoter methylation was assessed using methylation-Specific PCR, and expression of
SOX2
,
DNMT3b, TET3
, miR-200b-3p, and
TGFβ1
was quantified by qPCR.
Results
Aberrant methylation of the
SOX2
promoter, linked to increased expression, was observed in the BC cohort. Notably, several samples exhibited a poised promoter state, reflecting an epigenetic configuration associated with stemness. Upregulation of
DNMT3b
in miR-200b-reduced cells was significantly associated with
SOX2
promoter methylation, suggesting a feedback loop modulating methylation dynamics. Additionally, a positive association between deregulated
TET3
and
TGFβ1
highlights a positive feedback loop in the dynamic tumor microenvironment.
SOX2
methylation emerged as a strong prognostic marker, characterized by a low hazard ratio and high diagnostic sensitivity. Its combination with
DNMT3b
improved specificity (SE = 90%, SP = 79%). Reduced
TET3
and miR200b expression correlated with poor outcomes, and their integration with SOX2 formed a tri-gene signature that enhanced patient stratification. Correlation analyses revealed coordinated expression among
SOX2, TET3
, and
TGFβ1
, supporting their role in methylome regulation.
Conclusion
The findings underscore the clinical significance of this axis and its embedded feedback circuits in shaping BC progression and therapeutic response.