## 5 Breast Cancer and Current Treatment Strategies
An alternative strategy to achieving antiestrogenic effects involves inhibiting aromatase, the enzyme responsible for converting androgens into estradiol and estrone [195; 196; 197]. Aro-matase inhibitors (Als) are used to treat postmenopausal women with hormone-positive breast cancer, where the primary source of estrogen is aromatase activity in tissues such as the breast, bone, vascular endothelium, and central nervous system [193]. Als are typically categorized into steroidal (type 1) or nonsteroidal (type 2) inhibitors. In the absence of estrogen, certain growth factors can activate estrogen receptors, establishing an alternative pathway that promotes endocrine-resistant breast tumors [198]. This activation occurs via phosphorylation of a specific domain in the ER known as the activating function (AF1), triggered by a cascade of kinase-mediated events [199; 200]. A critical therapeutic target in oncology is the human epidermal growth factor receptor (EGFR) [201]. EGFR comprises four transmembrane tyrosine kinases: EGFR1/ErbB1, HER2/ErbB2, HER3/ErbB3, and HER4/ErbB4. When HER2 is overexpressed--occurring in 20-30% of aggressive breast cancer cases--it can lead to resistance to hormone therapies, particularly Tamoxifen [202]. HER2 inhibitors include small molecules from various chemical classes and monoclonal antibodies designed to target the receptor [203]. A key example is Trastuzumab (Herceptin(r)), a humanized monoclonal antibody that binds to the extracellular domain of the HER2 receptor, causing its internalization and degradation [204; 205]. Targeting EGFR with small-molecule inhibitors is a promising cancer therapy approach [206; 207]. Despite their initial success, the emergence of EGFR mutations presents a significant challenge to the efficacy of these drugs. Imatinib, approved in 2001, was the first EGFR-TKI, followed by Gefitinib in 2003 and Erlotinib in 2004, specifically targeting NSCLC. Lapatinib was approved in 2007 for breast cancer treatment. In the 2010s, seven FDA-approved EGFR-TKIs emerged, including Afatinib, Brigatinib, and Osimertinib. Additionally, four non-FDA-approved EGFR-TKIs, such as Icotinib and OImutinib, were introduced in China and South Korea. Other promising biological targets that are integral to cancer cell biology and are currently the focus of extensive research for the development of new compounds with potential anticancer activity include topoisomerase, kinase inhibitors, microtubule-targeting agents (MTAs), gene expression modulators and others. Topoisomerases are crucial enzymes in DNA replication and key targets for topoisomerase inhibitors (TOPO I and II), a vital class of anticancer drugs used to treat various solid tumors, including metastatic breast cancer [208; 209]. These inhibitors disrupt DNA strand management during replication, causing cytotoxic effects in cancer cells. Anthracyclines, a foundational class of topoisomerase inhibitors, include clinically significant derivatives such as Doxorubicin, Epirbucin, and Daunorubicin. Doxorubicin, notably versatile, is effective against breast cancer, leukemia, lymphoma, sarcomas, and other cancers [210; 211]. Synthetic anthracendiones, such as Mitoxantrone, target TOPO II, while acridine derivatives like Amsacrine inhibit topoisomerases [212; 213]. Camptothecn derivatives, including Topotecan and Irinotecan, target TOPO I, and epipodophyllotoxins like Etoposide disrupt TOPO II, interfering with DNA replication in cancer cells [214; 215]. Tubulin is a key protein involved in cell division and intracellular transport, making it an important target in cancer therapy [216]. Inhibiting tubulin's role in microtubule formation induces apoptosis, with microtubule-targeting agents (MTAs) disrupting mitosis and arresting cells during interphase [217]. MTAs interact with tubulin at four key binding sites: Laulimalide, Taxane/Epothilone, Vinca Alkaloid, and colchicine. These agents disrupt microtubule dynamics, halting cell division and promoting cancer cell death [218; 219; 220; 221].