Transcriptional coactivator MED1 in the interface of anti-estrogen and anti-HER2 therapeutic resistance

Abstract

Breast cancer is one of the most common cancer and leading causes of death in women in the United States and Worldwide. About 90% of breast cancers belong to ER+ or HER2+ subtypes and are driven by key breast cancer genes Estrogen Receptor and HER2, respectively. Despite the advances in anti-estrogen (endocrine) and anti-HER2 therapies for the treatment of these breast cancer subtypes, unwanted side effects, frequent recurrence and resistance to these treatments remain major clinical challenges. Recent studies have identified ER coactivator MED1 as a key mediator of ER functions and anti-estrogen treatment resistance. Interestingly, MED1 is also coamplified with HER2 and activated by the HER2 signaling cascade, and plays critical roles in HER2-mediated tumorigenesis and response to anti-HER2 treatment as well. Thus, MED1 represents a novel crosstalk point of the HER2 and ER pathways and a highly promising new therapeutic target for ER+ and HER2+ breast cancer treatment. In this review, we will discuss the recent progress on the role of this key ER/HER2 downstream effector MED1 in breast cancer therapy resistance and our development of an innovative RNA nanotechnology-based approach to target MED1 for potential future breast cancer therapy to overcome treatment resistance.

Keywords: HER2; MED1; RNA nanotechnology; estrogen receptor; therapy resistance; transcription cofactor.

Figure 1

Transcription coactivator MED1 as a central crosstalk point of ER and HER2 pathways. Transcriptional activator MED1 directly interacts with ER to bridge it with RNA polymerase II and transcriptional machinery to initiate gene transcription and mediate ER functions in breast cancer. MED1 also coamplifies with HER2 and is activated by HER2 signaling cascades through phosphorylation to promote breast cancer growth, metastasis, stem cell expansion, and therapeutic resistance. Adapted from Yang et al.^[55] Cell Reports.

Figure 2

Molecular mechanisms of HER2 and MED1 in anti-estrogen treatment resistance. In endocrine-sensitive breast cancer cells, treatment with anti-estrogen tamoxifen results in the recruitment of co-repressors to suppress gene transcription. However, when MED1 is overexpressed and phosphorylated by growth factor cascades such as HER2, the MED1/Mediator complex rather than ER co-repressors is recruited to activate gene transcription and render endocrine resistance. Adapted from Leonard et al.^[72], JZUS-B.

Figure 3

Overcoming breast cancer therapeutic resistance by MED1 targeting multifunctional RNA nanoparticles. The figure shows the atomic force microscopy (A) and schematic (B) of the pRNA-HER2apt-MED1siRNA nanoparticle, its tumor-specific uptake in vitro and in vivo (C), and therapeutic effect to inhibit endocrine-resistant tumor growth (D), cancer stem cell formation (E), and lung metastasis (F) in vivo in an orthotopic xenograft mouse model. **P < 0.01, ***P < 0.001. Adapted from Zhang et al.^[88], ACS Nano.