The role of histone deacetylase 3 in breast cancer

Selective HDAC3 Inhibitors with Potent In Vivo Antitumor Efficacy against Triple-Negative Breast Cancer

“…HDAC3, a class I HDAC isoform, is well known to be involved in various phases of breast cancer development. HDAC3 overexpression leads to various stages of disease progression such as proliferation, apoptosis, angiogenesis, cell cycle regulation, and metastasis . Higher levels of HDAC3 expression were found particularly in TNBCs than in non-TNBCs. ,, Literature reports established the key role of HDAC3 in various pathways where HDAC3 selective inhibition or knockdown led to the upregulated expression of p53 acetylation and enhanced p21 mRNA levels, leading to cell cycle arrest and eventually leading to apoptosis. , HDAC3 expression was found to be linked to cancer stem cell homeostasis by increased β-catenin expression via the Akt/GSK3β pathway .…”

“…Higher levels of HDAC3 expression were found particularly in TNBCs than in non-TNBCs. ,, Literature reports established the key role of HDAC3 in various pathways where HDAC3 selective inhibition or knockdown led to the upregulated expression of p53 acetylation and enhanced p21 mRNA levels, leading to cell cycle arrest and eventually leading to apoptosis. , HDAC3 expression was found to be linked to cancer stem cell homeostasis by increased β-catenin expression via the Akt/GSK3β pathway . HDAC3 inhibition or knockdown using si RNAs led to reduced ERα (estrogen receptor alpha) mRNA protein levels and stability leading to decreased proliferation in breast cancer cells. , Many other recent reports using HDAC3 selective inhibitors have established the critical role of HDAC3 in the in vitro as well as in vivo models of breast cancer. ,,,− The structure and regulatory mechanisms of HDAC3 are well established, and therefore, the discovery and development of selective HDAC3 inhibitors have become the most promising therapeutic strategy against various cancers …”

“…Breast cancer is one of the most commonly diagnosed cancers, accounting for the second most cancer-related deaths in women worldwide. , Breast cancer is a heterogeneous disease that is caused due to both genetic and epigenetic changes . Based on its gene expression profiling and molecular characteristics, breast cancer can be divided into four subtypes, i.e., luminal A (an estrogen receptor (ER)/progesterone receptor (PR)-positive and human epidermal growth factor receptor 2-negative; ER+, PR+, HER2−), luminal B (ER+, PR+, HER2+), human epidermal growth factor receptor 2-positive (HER2+), and triple-negative breast cancer (TNBC) (ER–, PR–, HER2−) . Among these, TNBC accounts for almost 15% of all breast cancer types characterized by poor prognosis, and high rates of metastasis along with a high risk of relapse resulting in overall lower survival rates …”

“…So far, four HDAC is (vorinostat, belinostat, romidepsin, and chidamide) have been clinically approved for the treatment of specific hematologic cancers . Further, several other small-molecule HDAC is are being explored for the treatment of a variety of hematological malignancies as well as solid tumors. ,− The clinical efficiency of the reported HDAC is is known to be limited in hematologic tumors and also has a poor manifestation in solid tumors as there are no clinically approved HDAC is for the treatment of solid tumors. , Major limitations of the existing HDAC is in solid tumors such as breast cancer and colorectal cancer might be a poor pharmacokinetic profile and less metabolic stability of the molecules. ,,, Moreover, because of their non-specificity against different HDAC isoforms, the treatment with HDAC is may often lead to several adverse effects and dose-related toxicities. Therefore, identifying and developing isoform-selective HDAC i s with improved metabolic stability and pharmacokinetic profile has been the main objective of researchers in this area of epigenetic drug discovery.…”

“…With these encouraging results, we propose that the modification in either cap and linker region of the reported lead molecule might offer improved HDAC3 selectivity and potency with improved druggable properties. With the established role of HDAC3 in breast cancer and its higher levels of expression in TNBCs, more specific HDAC3 inhibition could provide better targeted therapy for breast cancer, particularly TNBCs. ,, …”