MED23 in endocrinotherapy for breast cancer

Abstract

We investigated the role of the transcriptional mediator subunit 23 (MED23) in everolimus drug resistance, invasion and metastasis during breast cancer treatment and its molecular mechanism. We also evaluated the endocrinotherapy and prevention method for breast cancer. Breast cancer cell strains were established that can continuously express MED23, as well as inducible MED23-shRNA expression plasmids. The inductive agent, doxycycline (Dox), was added to the water for long-term silencing of MED23 in intratumoral cells. We conducted experiments on the role of MED23 in the regulation of invasion and metastasis of breast cancer using cell culture, western blotting, MTT proliferation experiment, fluorescent quantitative PCR and chromatin immunoprecipitation (ChIP). The silencing of MED23 significantly inhibited cellular growth and proliferation as well as soft agar cloning. Silencing of MED23 strengthened the sensitivity of the everolimus-resistant breast cancer cell strains BT474 and MCF-7/ADM cells to everolimus medication. The silencing of MED23, in combination with everolimus, inhibits the cell cycle progress of breast cancer cells. ChIP indicated that the mutual regulation of HER2 and MED23 also participates in the formation of the everolimus drug resistance mechanism. Therefore, MED23 plays an important role in everolimus drug resistance, invasion, and metastasis of breast cancer. As a potential molecular therapeutic target of breast cancer, MED23 overcomes drug resistance in clinical endocrinotherapy and controls the distal relapse and metastasis in breast cancer by the targeted silencing of MED23.

Novel mutation in the MED23 gene for intellectual disability: A case report and literature review

“…This gene is a key regulator of the protein‐coding gene expression and is involved in adipogenesis, chromatin modification, neural differentiation, proliferation, smooth muscle cell differentiation, and tumorigenesis . Mutations in this gene have been associated with several disorder, including cancer as well as, cardiovascular and neurodevelopmental diseases . Loss of function of the MED23 gene in the early developmental stages causes neurological disorders, whereas somatic mutations and variations in expression levels, play roles in the development of different kind of cancer later in life, including breast cancer, lung cancer, liver cancer, esophageal cancer, and Colorectal cancers …”

“…5,22,26 Mutations in this gene have been associated with several disorder, including cancer as well as, cardiovascular and neurodevelopmental diseases. 10,27,28 Loss of function of the MED23 gene in the early developmental stages causes neurological disorders, whereas somatic mutations and variations in expression levels, play roles in the development of different kind of cancer later in life, including breast cancer, lung cancer, liver cancer, esophageal cancer, and Colorectal cancers. 22,28,30 So far, only four variants in theMED23 have been associated with an autosomal recessive form of ID and refractory epilepsy.…”

Role of the Mediator Complex and MicroRNAs in Breast Cancer Etiology

“…Moreover, MED19 overexpression can enhance BC cell proliferation, cell invasion, epithelial-mesenchymal transition, and cell migration both in vivo and in vitro [ 77 ]. Additionally, MED19 can interact with EGFR and activates the EGFR/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, which in turn induces carcinogenesis and BC progression [ 78 ].…”

“…This subunit has been shown to be part of the Tail module of MED complex ( Figure 3 ) and it is a critical coactivator for the expression of ER-dependent target genes and growth of the estrogen-dependent BC cells [ 78 ]. MED23 is a binding target of ER and can bind to ER through two LxxLL motifs present at the N-terminus of MED23 and bridges the RNA polymerase II transcription machinery to regulate the expression of ER-dependent target genes [ 78 ]. It also participates in the formation of tamoxifen-resistance, a drug used to treat ER+ BC and its high expression is associated with poor prognosis of BC patients [ 78 ].…”

“…MED23 is a binding target of ER and can bind to ER through two LxxLL motifs present at the N-terminus of MED23 and bridges the RNA polymerase II transcription machinery to regulate the expression of ER-dependent target genes [ 78 ]. It also participates in the formation of tamoxifen-resistance, a drug used to treat ER+ BC and its high expression is associated with poor prognosis of BC patients [ 78 ]. Recently, it has been shown that silencing of MED23 significantly inhibits cellular growth and proliferation of BC cell lines (BT474 and MCF-7) and renders everolimus-resistant BC cells sensitive to the treatment with this drug [ 78 ].…”