Small molecule HDAC inhibitors: Promising agents for breast cancer treatment
Graphical abstract
Introduction
Breast cancer, a heterogeneous disease, is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide [1]. Broadly, based on the gene expression profiling, breast cancer can be sub-classified into four intrinsic subtypes: luminal A, luminal B (Luminal B1 and Luminal B2), HER2 enriched, and basal-like (Table 1) [2]. When separating luminal A from luminal B1 subtypes, the cutoff point of Ki-67 was 14% previously. But recently, this cutoff was changed in 20% [3]. Enrichment of GATA3, PIK3CA and MAP3K1 mutations were commonly identified in the luminal A subtype [4]. GATA3 mutation was found to be significantly associated with improved overall survival [5]. In luminal B1 subtype, the frequency of p53 mutations was higher than luminal A, but PIK3CA mutation frequency was lower [6]. As reported, nearly half of HER2 positive breast cancer subtype was Luminal B2 subtype, which overexpressed GATA3, BCL2, and ESR1 genes [7]. In HER2 positive subtype, the overexpressed genes in Luminal subtype were down-regulated or deleted. But ERBB2 and GRB7 genes were overexpressed in 17q22.24 ERBB2 amplicon. Triple negative breast cancer (TNBC) represents 15–20% of all breast cancers and is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival [8]. Based on its heterogeneity, TNBC can be classified into six molecular subtypes: 2 basal like classes (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem cell (MSL) and the luminal androgen receptor (LAR) class (Fig. 1) [9]. AR, EGFR, and BRCA1 might be unique biomarkers for targeted therapy and prognosis in TNBC [10]. Nowadays, genomic advancements provide opportunities for precision medicine, based on the biomarkers for specific breast cancer subtype.
Section snippets
HDACs and their mechanism of action
Epigenetic abnormalities are considered one of the hallmarks of cancer development and progression, and have emerged as novel therapeutic targets [11]. As primary protein components of chromatin, histones (H1, H2A, H2B, H3 and H4) play important roles in establishing interactions between the nucleosomes [12]. There are at least eight types of histone post-translational modifications, namely acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, ADP ribosylation, deamination and
HDACs and breast cancer
Impairment in the balance between HATs and HDACs has been reported in the development of breast cancer. In 2004, Zhang et al. found a higher expression of HDAC6 mRNA in hormone positive breast cancer patients with small tumors and low histologic grade, indicating more responsive to endocrine treatment and better prognosis [19]. Similarly, HDAC6 expression maybe an independent prognostic indicator for ER-positive patients who received adjuvant treatment with TAM, indicating the biological
Classification, structure–activity relationship (SAR) and quantitative structure–activity relationship (QSAR) of HDACIs
As HDACs-targeting inhibitors, HDACIs (histone deacetylase inhibitors) can enhance the acetylation of cellular proteins by blocking HDAC activity. Structurally, HDACIs are composed of a zinc binding group (ZBG), which chelates the zinc ion and engages in hydrogen bonds at the active site; a cap group, serving as a surface recognition motif; a hydrophobic cavity-binding linker region interacting with the HDAC substrate channel [29]. Based on the key function of the zinc catalytic domain, HDACIs
Pharmacokinetic and toxicological properties of the HDACIs
As anti-breast cancer agents, it is important to disclose the pharmacokinetic and toxicological properties of the HDACIs. In general, HDACs inhibition by HDACIs leads to inhibition of tumor growth, and apoptosis of cancer cells, whereas normal tissue is not particularly affected [38]. The biology of HDACIs transport is relevant to physiological and pharmacological benefits [39]. In 2013, Wilson et al. evaluated the effectiveness of HDACIs vorinostat and panobinostat in a dose- and
HDACs inhibitors for breast cancer treatment
Clinical trials using HDACIs have been performed and their results indicate that HDACIs have antitumor activity and may be clinically beneficial. Several HDACIs have been approved by the US FDA (Food and Drug Administration) for the treatment of several cancers, such as cutaneous T-cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL) and multiple myeloma (MM). However, no HDACI has been approved by the US FDA for breast cancer treatment. So far, 62 clinical studies have been registered in
Limitations and future direction of HDACIs
As shown, HDACIs seem to be a promising group of anti-cancer drugs, particularly in combination with other anti-cancer drugs and/or radiotherapy. However, the samples of the registered studies were relatively small. More promising evidence need to be obtained from large scale, multi-center clinical trials. Meanwhile, their use in the combination with other drugs and the schedule of such drug combinations need to be further investigated in both preclinical and clinical studies. Furthermore, it
Conclusion
HDAC inhibitors (HDACIs), the first successful epigenetic therapy against cancer, have been increasingly reported in breast cancer research. However, initial studies of HDACIs commonly failed to meet the desired response criteria. HDACIs have proven to be more useful in combination therapy, due to their favorable toxicity and ease of administration. In combination treatment, multiple oncogenic signaling pathways can be simultaneously targeted increasing the likelihood of overcoming resistance
Funding
This work was supported by The National Natural Science Foundation of China [No. 81572917, 81801920], China; Project of Xijing Hospital [No. XJZT18MJ30], China.
Declaration of Competing Interest
The authors declare that they do not have any conflict of interest.
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The author contributed equally to the work.