Targeting bromodomain and extraterminal proteins in breast cancer

Abstract

Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously. Here, we review the impact of inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers in breast cancer. These agents, including the prototypical BET inhibitor JQ1, have been shown to suppress a variety of oncogenic pathways while inducing minimal, if any, toxicity in models of several subtypes of breast cancer. BET inhibitors also synergize with multiple approved anti-cancer drugs, providing a greater response in breast cancer cell lines and mouse models than either single agent. The combined findings of the studies discussed here provide an excellent rationale for the continued investigation of the utility of BET inhibitors in breast cancer.

Keywords: ARV-825 PubChem CID 92044400; Anti-cancer drugs; BET inhibitor; BETd-246 PubChem CID 131698640; Breast cancer; Bromodomain and extraterminal protein; Drug synergy; I-BET151 PubChem CID 52912189; I-BET762 PubChem CID 46943432; JQ1 PubChem CID 46907787; MS417 PubChem CID 59190723; OTX015 PubChem CID 9936746; THZ1 PubChem CID 73602827; Transcriptional control; XD14 PubChem CID 52670832; dBET1 PubChem CID 91799313.

Figure 1. BET inhibitors suppress several oncogenic pathways in breast cancer

Binding of BETi to the BRD of BET proteins, such as BRD4, prevent BET proteins from binding to acetylated lysines in histone tails. This blocks BET protein localization to the promoter and enhancer regions of target genes, thus inhibiting their transcription. In breast cancer, outcomes of BETi include suppression of self-renewal properties in cancer stem cells, inhibition of hypoxia-induced pathways, altered metabolism, decreased metastatic potential, inhibition of angiogenic factors, and reduction in the pro-inflammatory response. In response to the disruption of several of these oncogenic pathways, breast cancer cells either undergo apoptosis or senescence.

Figure 2. Mechanisms of BET inhibitor resistance in breast cancer

A. Increased activity of the PI3K/AKT/mTOR pathway. Left: BET inhibition and normal PI3K/AKT/mTOR signaling. The binding of ligands, such as growth factors, hormones, or cytokines, to receptor tyrosine kinases (RTKs) activates PI3K. PI3K coverts PIP2 to PIP3, and PTEN counteracts PI3K by dephosphorylating PIP3. PIP3 mediates the phosphorylation, and thus activation, of AKT which leads to the activation of mTOR. mTOR signaling normally drives critical cellular process including cell growth, translation, and proliferation, but BETi suppress expression of the genes responsible for these processes. Right: The PI3K/AKT/mTOR pathway can remain active if PTEN is mutated, preventing it from converting PIP3 to PIP2, or if PI3K has an activating mutation. Both mutations increase phosphorylation of PIP3, maintaining activity of AKT and mTOR and overcoming BETi-mediated suppression of gene expression. B. Increased phosphorylation of BRD4. Left: BRD4 is phosphorylated by CK2 and dephosphorylated by PP2A. When BETi (blue circle) binds to BRD4, it prevents localization of BRD4 to the chromatin. BRD4 can thus no longer recruit Mediator to the DNA, silencing target gene expression. Right: Reduced PP2A activity increases the abundance of phosphorylated BRD4 (pBRD4). Despite the binding of BETi to its BRD regions, pBRD4 can still localize to the chromatin and interact with Mediator, maintaining transcription of target genes.

Figure 3. Combination treatments with BET inhibitors in breast cancer

Drugs that have been combined with BETi and resulted in greater efficacy are listed and color-coded according to the outcome of the combination treatment. Gray circles: drug synergized with BETi. Green circle: drug synergized with BETi, and the combination overcame tamoxifen resistance. Orange circle: drug synergized with BETi, and the combination overcame everolimus resistance. Purple circle: drug synergized with BETi, the combination overcame BETi resistance, and the combination prevented reactivation of the PI3K pathway. Yellow circle: the combination overcame and prevented lapatinib resistance. Red circle: drug synergized with BETi, and the combination overcame and prevented MEK inhibitor resistance.

Figure 4. The response of the hallmarks of cancer to BET inhibitor treatment in breast cancer

BETi impact most of the hallmarks of cancer described by Hanahan and Weinberg. An example of a BETi-induced effect is listed next to the hallmarks that were altered by BETi in breast cancer cells.