The pan-histone deacetylase inhibitor LBH589 (panobinostat) alters the invasive breast cancer cell phenotype

Abstract

Abstract. Triple-negative breast cancer (TNBC) is a very aggressive type of tumour and its aggressiveness is linked to E-cadherin downregulation. In estrogen-sensitive breast cancer, high levels of E-cadherin fit with high levels of ERα and MTA3 (a component of the transcription Mi-2/NuRD complex with intrinsic DAC activity). In TNBC the E-cadherin downregulation could be due to epigenetic silencing of the CDH1 gene as well as to the lack of a fully functioning ERα-activated pathway. We report that the pan-histone deacetylase inhibitor LBH589, a potent anti-proliferative agent, induced E-cadherin expression on cell membranes of MDA-MB-231 cells (TNBC), determining a reduction of cell invasion and migration. Even though E-cadherin expression in breast cancer is also regulated by estradiol and the ERα/MTA3/Snail/Slug pathway, LBH589 is able to increase E-cadherin without affecting the estrogen pathway. In fact, no expression of ERα, PR and FoxA1 was observed in MDA-MB-231 cells before and after LBH589 treatment; furthermore, the drug caused an increase in Snail and Slug expression with a concomitant reduction of MTA3 levels. Taking into consideration its anti-proliferative and anti-invasive properties, we suggest the use of LBH589 in aggressive breast cancer refractory to hormonal therapy. IntroductionBreast cancer, the most common cancer in women all over the world (1), is generally managed with success thank to available treatments (2). Regrettably, resistance to conventional therapy and increasing in metastatic and aggressive disease are emerging problems (3,4). A particular aggressive subtype of breast cancer is the triple-negative breast cancer (TNBC) that is defined by the absence of ER, PR and Her2/neu (5,6). TNBC generally occurs more frequently in younger women, frequently presents early metastatic spread and has poor overall prognosis (7,8).In breast cancer, as well as in other tumour types, epigenetic modifications are considered a crucial mechanism involved in cancer growth, dedifferentiation and aggressiveness; indeed, epigenetic deregulation can alter a number of molecular pathways involved in the control of cell function. Epigenetic drugs, able to restore normal epigenome in cancer cells, are under extensive pharmacological research (9). In breast cancer, histone acetylation state is considered of great importance. Histone acetylation and deacetylation, controlled by the enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs), affect chromatin conformation and, therefore, gene transcription, DNA repair and replication, and cell cycle checkpoints (10). Altered expression of HDACs has been reported in breast cancer by several authors (11,12). Therefore, HDAC inhibitors (DCI) are considered valuable therapeutic tools and have been under extensive evaluation. DCI vorinostat (13), for example, in association with paclitaxel and bevacizumab induced a partial or complete response in >50% of patients with metastatic breast cancer. The antiproliferative and re-differentiating effect of sev...

Suppression of triple-negative breast cancer metastasis by pan-DAC inhibitor panobinostat via inhibition of ZEB family of EMT master regulators

“…Our previous research and the work presented here demonstrate the ability of the pan-DAC inhibitor LBH589 (Panobinostat) to inhibit the expression of classical EMT-associated genes and induce expression of CDH1 in TNBC cell lines but not in luminal (Table 1) or basal A breast cancer cell lines [11]. These findings are supported by recent work by Fortunati et al that demonstrated LBH589 induction of CDH1 in MDA-MB-231 cells independent of estrogen receptor expression [49]. We also showed LBH589 to be much more potent in its anti-EMT effects than other known HDAC inhibitors, SAHA and TMP269.…”

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…Another study has confirmed these findings, given that it was found that in MDA-MB231 cells independent of estrogen receptor expression, panobinostat induced CDH1 expression (114). Panobinostat was reported to induce the expression of CDH1 and reduce the migration and invasion of TNBC cells.…”

Molecular Mechanism of the Cell Death Induced by the Histone Deacetylase Pan Inhibitor LBH589 (Panobinostat) in Wilms Tumor Cells

“…Vorinostat (suberoylanilide hydroxamic acid, SAHA), the first HDAC inhibitor for refractory and relapsed cutaneous T-cell lymphoma (CTCL) has been approved by FDA [ 45 , 46 ]. LBH589 is a novel pan HDACs inhibitor that possesses potent growth inhibitory activity in Ph(-) ALL cells [ 47 ], triple-negative breast cancer (TNBC)[ 24 ], hepatocellular carcinoma [ 29 ], prostate cancer (PCa) cells [ 48 ], relapsed/refractory Waldenstrom macroglobulinemia (WM) [ 49 ] and multiple myeloma (MM) [ 50 ]. However, to date, the molecular function of LBH589 in WT has remained unknown.…”

“…HDAC inhibitor LBH589 has demonstrated antitumor activity, including HDACs suppression and induction of tumor cell apoptosis in various human cancer models. In Triple-negative breast cancer (TNBC), LBH589 has anti-proliferative properties in aggressive breast cancer refractory to hormonal therapy [ 24 ]. In human renal cell carcinoma, LBH589 caused obvious cell cycle arrest in the G2/M phase and caused cell apoptosis [ 25 ].…”