OS03-01 Exploring the Role of YY1 in Clock Genes Regulation and Breast Cancer in Night Shift Workers

Breast cancer (BC) is the second leading cause of cancer-related mortality among women, with night shift work (NSW) identified as a significant risk factor due to its disruption of circadian rhythms. Since 2019, NSW has been classified as a Group 2A carcinogen by the IARC [1]. Prolonged exposure to NSW has been linked to increased risk of BC, primarily due to its effects on melatonin synthesis, which impacts anti-estrogenic and anti-oxidant properties [2]. The transcription factor Yin Yang 1 (YY1) plays a pivotal role in BC tumorigenesis by regulating the expression of key genes involved in oncogenic pathways 3, 4. In addition to its role in cancer, YY1 has been shown to modulate the expression of clock genes, influencing circadian rhythms that are potentially disrupted by NSW 5, 6. Occupational toxicology plays a critical role in assessing the long-term health risks associated with NSW, including its function as an occupational carcinogen through chronic circadian misalignment and endocrine disruption [7]. Our previous work demonstrated differential expression of 12 clock genes in BC diagnosed in NSW-exposed women, including marked over-expression of BHLHE40, CIART, CLOCK, PDPK1, and TIMELESS, and significant under-expression of HLF, NFIL3, NPAS3, PER1, PER3, SIM1, and TEF [8]. This study aims to further investigate the regulatory role of YY1 in BC development among night shift workers. Using the Nurse Health Study (NHS) gene expression dataset (GSE115577), we analyzed YY1 expression in both BC and normal breast tissue. Our results demonstrate that YY1 is upregulated in BC, especially in luminal and basal subtypes, and in grade 3 tumors. Additionally, receiver operating characteristic (ROC) analysis suggests that YY1 could serve as a predictive biomarker for BC risk in NSW workers. STRING networking revealed that YY1 directly interacts with key clock genes such as PDPK1, NFIL3, CLOCK, and BHLHE40, underscoring its involvement in circadian gene regulation in BC. HuRI mapping of protein-protein interactions in normal breast tissue further highlighted indirect interactions with other clock genes, including BHLHE40, CIART, NFIL3, and PER1, suggesting a broader regulatory network. PINA 3.0 analysis revealed that YY1 expression is correlated with key BC prognostic genes and interacts with critical BC driver genes, establishing YY1 as a central modulator of both circadian regulation and BC progression. In conclusion, these findings emphasize the crucial role of YY1 in regulating circadian pathways in BC, particularly among NSW-exposed women, and suggest that YY1 may serve as both an early detection biomarker and a therapeutic target. Further validation studies are needed to confirm these computational predictions and assess their clinical applicability for improving BC prevention and treatment in night shift workers, reinforcing the need for a stronger occupational toxicology framework to mitigate long-term health risks associated with NSW.