الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Breast cancer is a disease with a major worldwide burden. It is the most frequently diagnosed cancer among women worldwide and the second leading cause of cancer death after lung cancer among women. While opportunities of being cured of breast cancer have increased, metastatic breast cancer remains incurable and accounting for the majority of breast cancer mortality globally.
Breast cancer is a very complex heterogeneous disease with variable clinical behaviors. it isn’t the same for every woman. Moreover, it is not the same at the cellular level in the same women which called intratumor heterogeneity. Tumor progression and resistance to therapy are predominantly driven by acquired genetic mutations which if discovered in time can switch patient treatment and consequently the outcome. Solving the mystery of heterogeneity is the key to manage breast cancer successfully with totally different outcome and longer progression free survival.
Endocrine therapy is the mainstay therapy to manage breast cancer even in the metastatic setting since ER+ breast cancer is the most frequent breast cancer subtype. A functional ER is a must to achieve successful management of cancer growth by endocrine therapy. Unfortunately, resistance to ET is inevitable in the majority of patients creating a major challenge in breast cancer management especially in the metastatic setting. Discovery of the mechanisms of endocrine resistance could improve the management of breast cancer by using another effective drug to overcome endocrine resistance.
Recently, various studies uncover mutations in ESR1, the gene encoding the ER in patients with ER positive metastatic breast cancer who received endocrine therapies. These mutations are clustered in ligand binding domain (LBD) of the ER leading to tumor growth by independent ER activity. Thus, ESR1 mutations could account for a mechanism of endocrine resistance in those patients.
The acquisition of ESR1 mutations under the selective pressure of endocrine therapy in breast cancer patients alters the conformation of ER with subsequent alteration in function. Mutations at residues 536–538 (D538G, Y537S) in particular, promote ER activity without a ligand, resulting in resistance to endocrine therapy.