Action of Estrogen In Breast Cancer: A review Study
Keywords:breast cancer, ER receptors, estrogen metabolism, endocrine resistance
Estrogen hormone is one of the steroid hormones has a critical role in breast cancer etiology. It has been implicated in proliferation and differentiation of cells through its action promoting binding of its receptor to DNA, changing transcriptional expression of target genes. In addition to the classical DNA binding mechanism, estrogen can also regulate gene expression through a nongenomic mechanism associated with activation a variety of signal transduction pathways (e.g. PI3`K/AKT, ERK/MAPK, PLC/PKCs , p38/MAPK). Dysregulation of the balance between pro-apoptotic and anti-apoptotic members of the Bcl-2 family, would result in apoptosis inhibition and tumorigenesis. Also, poor responses towards hormonal therapy, radiotherapy, and chemotherapy and treatment resistance are likely caused by dysregulation of apoptosis. Importantly, E2 has been shown to prevent apoptosis, first through its action in activation of anti-apoptotic proteins like Bcl-xl and Bcl-2 in breast cells like MCF-7, T47D and ZR-75-1 or due to its metabolites independently of ER. Estrogen metabolism includes several very important pathways that can possibly induce de novo DNA mutation. These pathways include:2, &4-hydroxylation, 16 α hydroxylation and 4 hydroxyestradiol-quinone-adenine/guanine adduct depurination, which subsequently participate in DNA damage that can lead to breast cancer. Endocrine resistance is considered one of the most permanent problems that can reduce the benefits of breast cancer treatment. Alteration of microRNAs expression, polymorphisms occuring in tamoxifen metabolism, and using reduntant alternative signaling pathways, resulting in poor treatment responses of breast cancer patients and induction of endocrine resistance.Thus, most proposed therapeutic strategies will be based on a combination of drugs targeting various pathways alongside endocrine therapy that may improve the outcomes of endocrine responses in resistant breast cancer cells.
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