Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 171 Non-Coding RNAs: Non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are key regulators of gene expression. In breast cancer, miRNAs can function as oncogenes or tumor suppressors by targeting mRNAs for degradation or translational repression (Baylin and Jones, 2016; Davalos and Esteller, 2023). For example, miR-21 is often upregulated in breast cancer and promotes tumor growth by inhibiting the expression of tumor suppressor genes (Szczepanek et al., 2023). Conversely, miR-34 acts as a tumor suppressor and its downregulation is associated with poor prognosis. 4.3 Interaction between genomic and epigenetic factors The interplay between genomic and epigenetic alterations is a critical aspect of breast cancer pathogenesis. Epigenetic changes can influence genomic stability and contribute to the accumulation of genetic mutations. Epigenetic Regulation of DNA Repair Genes: Epigenetic modifications can affect the expression of genes involved in DNA repair mechanisms. For instance, hypermethylation of the BRCA1 promoter leads to reduced expression of this gene, impairing the homologous recombination repair pathway and increasing the likelihood of genomic instability (Davalos and Esteller, 2023). This can result in the accumulation of mutations and chromosomal aberrations, driving cancer progression (You et al., 2012). Histone Modifications and Chromatin Structure: Histone modifications can alter chromatin structure and accessibility, influencing the repair of DNA damage. For example, histone acetylation generally leads to an open chromatin conformation, facilitating the access of DNA repair machinery to damaged sites. Conversely, histone deacetylation can result in a closed chromatin state, hindering DNA repair processes and promoting genomic instability (Sharma et al., 2010; Gray et al., 2022). Non-Coding RNAs and Genomic Stability: Non-coding RNAs also play a role in maintaining genomic stability. miRNAs can regulate the expression of genes involved in DNA damage response and repair. Dysregulation of these miRNAs can lead to defective DNA repair and increased mutation rates (Baylin and Jones, 2016; Szczepanek et al., 2023). For example, the downregulation of miR-34, which targets genes involved in cell cycle regulation and apoptosis, can contribute to genomic instability and cancer progression. In conclusion, the intricate interplay between genomic and epigenetic alterations is fundamental to the pathogenesis of breast cancer. Understanding these interactions provides valuable insights into the mechanisms driving tumorigenesis and offers potential avenues for therapeutic intervention. 5 Genetic Heterogeneity and Subtype Specificity 5.1 Luminal subtypes and genetic features Luminal subtypes of breast cancer, specifically Luminal A and Luminal B, are characterized by distinct genetic profiles that influence their behavior and response to treatment. Luminal A tumors generally exhibit lower proliferation rates and better prognosis compared to Luminal B tumors. Genetic alterations commonly observed in Luminal A subtypes include mutations in the PIK3CA gene and low expression of proliferation-related genes. These tumors are typically hormone receptor-positive (HR+) and HER2-negative, which makes them responsive to endocrine therapies (Prat et al., 2015). In contrast, Luminal B tumors are more aggressive, with higher proliferation rates and a worse prognosis. They often exhibit higher expression of proliferation-related genes and may also present with PIK3CA mutations, although at a lower frequency compared to Luminal A. Additionally, Luminal B tumors can be either HER2-positive or HER2-negative, which influences their treatment strategies. The presence of HER2 amplification in Luminal B tumors necessitates the use of HER2-targeted therapies in addition to endocrine treatments (Prat et al., 2015). 5.2 HER2-Enriched subtype HER2-positive breast cancer is a heterogeneous disease that includes various intrinsic molecular subtypes, with the HER2-enriched (HER2-E) subtype being the most prevalent. HER2-E tumors are characterized by high expression of genes located near the HER2 amplicon on chromosome 17, including ERBB2, which encodes the
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