Abstract P5-01-18: ESRα and RASSF1A promoter methylation changed significantly in benign tumors and in the early event of breast cancer progression

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Abstract Methylation in the estrogen receptor alpha (ESRa) promoter is an epigenetic abnormality in breast cancer (BCa) and hypermethylation-mediated loss of ESRa expression could provide the cell with growth-promoting characteristics such as insensitivity to antigrowth signals. To investigate if there is a direct link between P0/P1 promoters of ESRa aberrant methylation and risk of progression of the fibroadenoma and fibrocystic diseasee to BCa. Methodology: We used pyrosequencing to assess the DNA methylation in a panel of genes (ESRa, RASSF1A, and HIN1) in benign and cancerous human breast tissues and BCa cell lines. Results: There was a significant elevated level of DNA methylation in ESRa P1 promoter (P=0.0001) in fibroadenoma tissues than ER-negative BCa, and 2-fold increase ESRa expression in fibrocystic, and fibroadenoma. HIN1 and RASSF1A methylation were elevated in ER-positive when compared to ER-negative BCa (P-value<0.5). To check if DNA methylation influence multiple gene networks rather than a single gene, we assessed the interaction between DNA methylation and the 3 genes within several types of breast tissues (fibroadenoma, and ER-positive and ER-negative BCa). Two-way ANOVA Univariante analysis of variance revealed a significant interaction between gene and breast types. ANOVA mixed model was further performed and revealed a significant interaction between the RASSF1A gene with fibroadenoma and ER-positive BCa (P-value=0.004). ESRa prmoter methylation in ER-positive BCa is associated with molecular subtypes (P-value=0.014) and grade (P-value=0.022). Tumors with unclassified molecular subtypes (ER-positive, PR-negative, HER2-negative) had elevated levels of methylation (P-value=0.046) in the P0 promoter compared with luminal B (ER-positive, PR-positive, HER2-positive) tumors. Tumors with grade 3 showed a bordeline association with ESRa P1 promoter methylation when compared with grade 2 tumors (P-value=0.056). These results showed a highly methylated ESRa P0 promoter in the initial stages of breast carcinogenesis while the methylation in the P1 promoter occurs at later stages of BCa with poor prognosis. Conclusion: These findings suggest that methylation of ESRa promoter and tumor-related genes occured in pre-invasive lesions as an early event in BCa progresson. Furthermore, methylation of ESRa promoters could be consider a biomarker for the development of a diagnostic test that could predict benign breast disease that are at elevated risk of progressing to BCa. Citation Format: Yasmine Kanaan, Sylvia Dasi, Bernard Kwabi-Addo, Desta Beyene, Robert L DeWitty jr, Kelly Bolden, Steven Nagel, Robin Williams, Babak Shokrani, Tammey J Naab, Olakunle O Kassim, Robert L. Copeland, Victor Apprey, Kelly Bolden, Andrea Hayes-Dixon. ESRα and RASSF1A promoter methylation changed significantly in benign tumors and in the early event of breast cancer progression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-01-18.

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