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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• Breast Cancer and Epigenetics, A Look at the Development and Progression

• Yasaman Baharvand ,^1,* Saeid Reza Khatami,² Narges Mousavi,³
  1. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
  2. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
  3. Midwifery Department, Faculty of nursing and midwifery ahvaz jondishapur university of medica sciences
  
  
  
• Introduction: Breast cancer is currently among the most commonly diagnosed cancers (1). The incidence of invasive breast cancer has been rising since 2004. Approximately 80% of all breast cancer cases are classified as estrogen receptor-positive (ER+) (2). Epigenetic modifications refer to heritable changes in gene expression that occur without alterations to the DNA sequence and the most important routs include DNA methylation, histone modification, X-chromatin remodeling, non-coding RNA, nucleosome localization, and genomic imprinting (3). Histone modifications, including acetylation, deacetylation, and methylation, have been extensively studied in breast cancer. Histone acetylation adds an acetyl group from acetyl-CoA to the lysine amino group. Deacetylation removes acetyl groups from lysine residues in histone tails, leading to condensed chromatin and gene repression. Methylation adds a methyl group to lysine or arginine residues in histone tails (4). During histone acetylation the addition of an acetyl group to lysine residues on histone tails, neutralise their positive charge. This weakens the interaction between negatively charged DNA and histones, leading to chromatin decondensation and a transcriptionally active state. Removal of the acetyl group reverses this effect, causing chromatin condensation and transcriptional repression. Histone methylation alters residue basicity and hydrophobicity, which can affect DNA–protein interactions, including transcription factor binding. Histone methyltransferases (HMTs) catalyze methylation (5). DNA methylation is the addition of a methyl group to the 5-carbon of cytosine within CpG dinucleotides. These changes would be critical in cancer initiation and progression by disrupting gene regulation (6). Abnormal DNA methylation is a hallmark of tumorigenesis, often affecting promoter regions, where it silences tumor suppressor genes or activates oncogenes (7). Promoter hypermethylation and global DNA hypomethylation are common in cancer (8). Whole-genome studies have revealed a correlation between DNA methylation patterns and breast cancer pathogenesis, identifying 345 methylated genes across 40 breast cancer lines. Holm et al. linked methylome variation to breast cancer heterogeneity, finding differential methylation in about 18,700 genes associated with CpG sites regions where cytosine is followed by guanine in the 5′ → 3′ DNA strand and unlike other cancers, breast cancer shows gene body hypomethylation (4). Aberrant DNA methylation drives cancer through regional hypermethylation, which silences tumor suppressor genes, and global hypomethylation, which activates oncogenes. These processes involve DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes acting on CpG sites, including promoter CpG islands (9). MicroRNAs (miRNAs) can also regulate estrogen receptor (ER) expression, playing key roles in both normal breast development and tumor formation. For example, miRNA-142-3p, miRNA-335-5p, miRNA-21, and miRNA-192-5p downregulate ER, while miRNA-148a suppresses DNMT1, leading to ER upregulation in MCF-7 cells. Conversely, miRNAs like miRNA-27a act oncogenically by promoting ER overexpression and advancing cancer progression (4).
• Methods: Relevant literature was collected through a search of databases including PubMed and Google Scholar. Articles published between 2019 and 2025 were included to ensure up-to-date findings. Keywords such as “Breast cancer”, “Histone modifications”, “DNA methylation”, “miRNA” and “Epigenetics” were used.
• Results: Aberrant DNA methylation plays a major role in breast cancer, from early tumorigenesis to metastasis. Early methylation changes affect genes involved in cell differentiation, DNA binding, homeobox proteins, and transcription signaling, promoting tumor-supportive traits in breast cancer stem cells. In early basal-like breast carcinogenesis, around 800 low-activity promoters are hypermethylated including 48 gene sets linked to cancer, polycomb regulation, and transcription factors, while about 280 high-activity promoters are hypomethylated (5). Histone acetylation and methylation are the most widely studied histone modifications in breast cancer. Shifts in histone modification profiles, such as acetylation (H3K9ac, H3K18ac, H4K12ac, H4K16ac) and methylation (H4R3me2, H3K4me2, H4K20me3), have been linked to disease prognosis when comparing normal tissue to primary invasive carcinoma. miRNA dysregulation is also implicated at every stage of breast cancer progression, from tumor initiation to metastasis. Research into breast cancer related miRNAs has grown rapidly since 2005, with numerous reviews updating their role in disease biology (5).
• Conclusion: These findings underscore the importance of epigenetic mechanisms in breast cancer development, heterogeneity, and progression. The regulatory roles of DNA methylation, histone modifications, and miRNAs contribute not only to tumor behavior but also to potential diagnostic and therapeutic strategies. Continued exploration of epigenetic alterations offers valuable insights for precision medicine approaches aimed at early detection and targeted treatment of breast cancer.
• Keywords: Breast cancer, Epigenetics, Histone modifications, DNA methylation, miRNA