Therapeutic and Mechanistic Perspectives of Protein Complexes in Breast Cancer

Abstract

Breast cancer affects one in eight women making it the most common cancer in the United Kingdom, accounting for 15% of all new cancer cases. One of the main challenges in treating breast cancer is the heterogeneous nature of the disease. At present, targeted therapies are available for hormone receptor- and HER2-positive tumors. However, no targeted therapies are currently available for patients with triple negative breast cancer (TNBC). This likely contributes to the poor prognostic outcome for TNBC patients. Consequently, there is a clear clinical need for the development of novel drugs that efficiently target TNBC. Extensive genomic and transcriptomic characterization of TNBC has in recent years identified a plethora of putative oncogenes. However, these driver oncogenes are often critical in other cell types and/or transcription factors making them very difficult to target directly. Therefore, other approaches may be required for developing novel therapeutics that fully exploit the specific functions of TNBC oncogenes in tumor cells. Here, we will argue that more research is needed to identify the protein-protein interactions of TNBC oncogenes as a means for (a) mechanistically understanding the biological function of these oncogenes in TNBC and (b) providing novel therapeutic targets that can be exploited for selectively inhibiting the oncogenic roles of TNBC oncogenes in cancer cells, whilst sparing normal healthy cells.

Keywords: PROTAC; TNBC; breast cancer; cancer therapy; post-translational modification; protein complexes; protein-protein interaction; transcription factor.

FIGURE 1

An overview of current and emerging agents for TNBC therapy. (A) TNBC therapies targeting the cell surface and cytoplasm. Cell surface therapies include inhibitors of immune tolerance inducing proteins such as PD1 and PD-L1. Cytoplasmic therapies include inhibitors of the Ras/MAPK pathway, especially MEK inhibitors, inhibitors of the PI3K/AKT/mTOR pathway, inhibitors of the Hedgehog signaling pathway, and cell cycle inhibitors such as paclitaxel and CDK inhibitors. (B) TNBC therapies targeting the nucleus. These therapies tend to target DNA synthesis and repair pathways or affect DNA viability to induce cell-cycle arrest and cell death.

FIGURE 2

Potential mechanisms of transcription factor (TF) targeting for cancer therapy. (A) Inhibition of oncogenic TF expression. This may take the form of altering chromatin accessibility, through inhibitors of epigenetic machinery, or by disrupting the assembly of transcriptional machinery at the protein-protein or protein-DNA binding level. (B) Depletion of oncogenic proteins by PROTAC-mediated proteasomal degradation. A bi-functional molecule containing a protein of interest-binding region and an E3-ligase binding region links the protein of interest to an E3-ligase, leading to ubiquitination and proteasomal degradation. (C) Inhibition of TF function through modulation of post-translational modifications. Assembly of oncogenic transcriptional (or epigenetic) assemblies may rely on post-translational modifications. Inhibiting the enzymes responsible for these modifications or inhibiting the binding pocket of the specific modification may represent feasible options for preventing the assembly of oncogenic transcriptional assemblies. (D) Inhibition of mutation-dependent transcriptional assemblies. Structural information regarding the binding interfaces of mutated transcriptional or epigenetic proteins may allow for the design of therapies that inhibit mutation-dependent interactions and prevent the assembly of mutation-dependent transcriptional machinery.