Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 166-181 http://medscipublisher.com/index.php/cge 169 3.2 Hormonal pathways and breast cancer Hormonal pathways, particularly those involving estrogen receptors (ER), play a crucial role in the development and progression of breast cancer. Estrogen receptors are nuclear hormone receptors that, upon binding to estrogen, regulate the expression of genes involved in cell proliferation and survival. Approximately 70% of breast cancers are ER-positive, meaning they express estrogen receptors and rely on estrogen signaling for growth (Feng et al., 2008; Kashyap et al., 2021). The impact of estrogen on breast cancer is multifaceted. Estrogen promotes the proliferation of breast epithelial cells, and its prolonged exposure, such as through hormone replacement therapy, is a known risk factor for breast cancer. Additionally, estrogen signaling can interact with other oncogenic pathways, such as HER2 and PI3K/AKT, to enhance tumor growth and resistance to therapy (Hu et al., 2009; Hazra et al., 2021). Targeting estrogen receptors with therapies such as selective estrogen receptor modulators (SERMs) and aromatase inhibitors has been a cornerstone of breast cancer treatment, particularly for ER-positive tumors (Osborne et al., 2004; Kashyap et al., 2021). 3.3 Signaling pathways in cancer progression Several key signaling pathways are implicated in the progression of breast cancer, including the Wnt/β-catenin and HER2 signaling pathways. The Wnt/β-catenin pathway is involved in regulating cell proliferation, differentiation, and migration. Aberrant activation of this pathway, often through mutations in pathway components or epigenetic modifications, leads to increased β-catenin levels and transcription of target genes that promote tumorigenesis (Feng et al., 2008; Hazra et al., 2021). In breast cancer, dysregulation of the Wnt/β-catenin pathway has been associated with increased tumor aggressiveness and poor prognosis (Hazra et al., 2021). The HER2 signaling pathway, mediated by the ERBB2 gene, is another critical pathway in breast cancer. HER2 is a receptor tyrosine kinase that, when overexpressed, activates downstream signaling cascades such as the PI3K/AKT and MAPK pathways, leading to enhanced cell proliferation, survival, and metastasis (Kenemans et al., 2004; Hu et al., 2009). HER2-positive breast cancers are typically more aggressive and have a higher likelihood of recurrence. Targeted therapies such as trastuzumab (Herceptin) have been developed to inhibit HER2 signaling and have significantly improved outcomes for patients with HER2-positive breast cancer (Osborne et al., 2004; Hu et al., 2009). In summary, the molecular pathogenesis of breast cancer involves a complex interplay of genetic mutations in oncogenes and tumor suppressor genes, hormonal pathways, and key signaling pathways. Understanding these mechanisms is crucial for developing targeted therapies and improving clinical outcomes for breast cancer patients. 4 Genomic and Epigenetic Alterations 4.1 Somatic mutations in breast cancer Breast cancer is a heterogeneous disease characterized by a variety of somatic mutations that differ across its subtypes. Advances in high-throughput sequencing technologies have enabled the detailed molecular characterization of these mutations, revealing a complex landscape of genetic alterations. Somatic mutations in breast cancer include point mutations, insertions, deletions, and copy number variations, which can lead to the activation of oncogenes or the inactivation of tumor suppressor genes (Chakravarthi et al., 2016). For instance, mutations in the TP53 gene are prevalent in triple-negative breast cancer, while PIK3CA mutations are more common in hormone receptor-positive subtypes (Chakravarthi et al., 2016; Calabrese et al., 2020). The Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium has provided a comprehensive catalogue of cancer-associated gene alterations, including those in breast cancer. This study identified numerous somatic single-nucleotide variants and structural variants that drive tumorigenesis (Calabrese et al., 2020). The integration of transcriptome and whole-genome sequencing data has further elucidated the relationship between somatic mutations and gene expression, highlighting the role of non-coding regions in regulating gene activity (Calabrese et al., 2020) (Figure 2).
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