The Construction Of ERα Expression Vector Containing Vitamin D₃ Response Elements, And Its Effects On ER-negative Breast Cancer Cells In Combination With Tamoxifen

Breast cancer is the most common noncutaneous cancer among women in the world. Although its mortality has declined in developed countries over the last decade, it is still the second leading cause of cancer-related deaths in women, only after lung cancer. Currently, various pharmacological strategies including antiestrogen therapy are used to ameliorate the proliferative effects of estrogens by interfering with the ER-involved surviving and proliferation-associated signalling pathway.The estrogen receptor(ER), a member of nuclear receptor superfamily, is a ligand- inducible transcription factor that mediates many of the estrogenic actions in target cells. Upon agonist binding, the ER undergoes conformational changes which lead to dissociation of heat shock proteins, dimerization, and binding to the DNA at estrogen response elements in regulated genes. Today, approximately 70% of all breast cancers are dependent for their growth on estrogen and on a functional estrogen receptorα(ERα). The steroid hormone estrogen is a key regulator of growth and development of normal breast tissue. This hormone also triggers metastatic activity of breast cancer cells by an unknown mechanism. In the target cell, estrogen exerts its effects by binding to intracellular estrogen receptor subtypes, ERαand ERβ. The hormone-occupied estrogen receptors(ER) bind to the estrogen-responsive DNA sequences in the genome and influence the expression of specific gene networks, which control cell proliferation and differentiation. ERαor ERβdisplays a range of transcriptional activities, depending on whether the receptor is occupied by hormone or synthetic analogs known as selective estrogen receptor modulators (SERMs).SERMs, such as Tamoxifen, mimic estrogen action in certain tissues while opposing it in others. Tamoxifen is one of the most commonly SERMs applied to breast cancer therapy,it behaves as an antiestrogen in the breast and exerts convincing anti-proliferation...