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Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer - PubMed

Review

Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer

Marissa Leonard et al. J Zhejiang Univ Sci B. 2019 May.

Abstract

Breast cancer, one of the most frequent cancer types, is a leading cause of death in women worldwide. Estrogen receptor (ER) α is a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer. About 75% of breast cancer cases are diagnosed as ER-positive; however, nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies. Recent studies have identified an ER coactivator, Mediator Subunit 1 (MED1), as a unique, tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance. MED1 is overexpressed in over 50% of human breast cancer cases and co-amplifies with another important breast cancer gene, receptor tyrosine kinase HER2. Clinically, MED1 expression highly correlates with poor disease-free survival of breast cancer patients, and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment. In this review, we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex, its crosstalk with HER2 in anti-estrogen resistance, breast cancer stem cell formation, and metastasis both in vitro and in vivo. Furthermore, we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.

Keywords: Mediator Subunit 1 (MED1); Mediator; Estrogen receptor; Breast cancer; Endocrine resistance; RNA nanotechnology.

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Conflict of interest statement

Compliance with ethics guidelines: Marissa LEONARD and Xiaoting ZHANG declare that they have no conflict of interest.

All institutional and national guidelines for the care and use of laboratory animals were followed.

Figures

Fig. 1
Fig. 1

MED1/Mediator complex in estrogen receptor (ER)-mediated gene transcription Ligand-bound ER recruits diverse transcriptional co-factors, such as chromatin remodeling factors, histone modifying enzymes, and ultimately the MED1/Mediator complex, to relay signal(s) to RNA polymerase II and general transcription factors (GTFs) to initiate targeted gene transcription. The ER directly interacts with Mediator through MED1 and its two classical LxxLL motifs/NR-boxes

Fig. 2
Fig. 2

Molecular mechanisms of HER2/MED1 crosstalk in anti-estrogen therapy resistance HER2-mediated phosphorylation and MED1 activation led to the recruitment of phosphor-MED1 and MED1/Mediator complex, instead of transcriptional co-repressors (N-CoR/SMRT), to the target gene promoter even in the presence of anti-estrogens such as tamoxifen

Fig. 3
Fig. 3

Targeting MED1 by pRNA nanoparticles to overcome anti-estrogen resistance of human breast cancer cells pRNA nanoparticles harboring a HER2-specific RNA aptamer and two siRNAs against MED1 were constructed and tested for efficacy both in vitro and in vivo in orthotopic xenograft models. These highly stable and bio-safe nanoparticles not only targeted the breast cancer cells specifically both in vitro and in vivo, but also immensely inhibited tumor growth, cancer stem cell formation, lung metastasis, and re-sensitized human breast cancer cells to anti-estrogen tamoxifen treatment. Scale bars: green, 10 nm; blue, 25 µm. Adapted with permission from Zhang et al. (2017), copyright (2017) American Chemical Society

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