The histone deacetylase inhibitor trichostatin A sensitizes estrogen receptor α-negative breast cancer cells to tamoxifen

Abstract

Many cases of breast cancer show loss of estrogen receptor (ER) a expression, which leads to unresponsiveness to antihormonal treatment even though there is no loss of the structurally and biochemically similar ER b. ER activity is positively and negatively regulated by transcriptional regulators such as histone deacetylase (HDAC), which is known to be a negative ER regulator. Here, we evaluated using ER b as an alternative target for tamoxifen therapy by treating ER a-negative, b-positive breast cancer cells with the HDAC inhibitor trichostatin A (TSA), and testing whether tamoxifen responsiveness increased following upregulation of ER b. TSA enhanced the overall ER transcriptional activity in these cells, as visualized by estrogen response element-regulated reporter and the expression of progesterone receptor, a known ER target, without ER a restoration. Additionally, TSA induced the expression and nuclear translocation of ER b but not a, suggesting that these actions leading to increase of ER transcriptional activity are mediated through ER b rather than a. Furthermore, following treatment with TSA, the formerly unresponsive MDA-MB-231 and Hs578T breast cancer cells became responsive to tamoxifen. However, reduction of ER b expression by short interfering RNA abrogated this TSA-induced sensitization effect in these cells. Together, these results show that the HDAC inhibitor TSA sensitized ER a-negative, antihormone-unresponsive breast cancer cells to tamoxifen treatment possibly by upregulating ER b activity.

Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086

“…Drug-induced changes in morphology and neutral lipid accumulation were more promptly elicited in ERa-positive MCF-7 cells while the decrease in mobility and active cathepsin D levels was especially observed in highly migrating ERa-negative MDA-MB-231 cells. Importantly, WEB-2086 effects were reversed upon drug removal to suggest that for potential therapeutic purposes carcinoma cells should receive the drug continuously as reported for other differentiation inducers such as butyrates (Guilbaud et al, 1990), TSA (Jang et al, 2004) and SAHA (Munster et al, 2001). Moreover, specific HDACi including valproic acid increased and/ or reactivated ERa expression (Yang et al, 2000;Graziani et al, 2003) and sensitize both ERa-positive and ERa-negative breast cancers to treatment with tamoxifen (Jang et al, 2004).…”

“…Importantly, WEB-2086 effects were reversed upon drug removal to suggest that for potential therapeutic purposes carcinoma cells should receive the drug continuously as reported for other differentiation inducers such as butyrates (Guilbaud et al, 1990), TSA (Jang et al, 2004) and SAHA (Munster et al, 2001). Moreover, specific HDACi including valproic acid increased and/ or reactivated ERa expression (Yang et al, 2000;Graziani et al, 2003) and sensitize both ERa-positive and ERa-negative breast cancers to treatment with tamoxifen (Jang et al, 2004). However, tamoxifen acts as an antioestrogen in breast, but as an oestrogen in the uterus, bone and cardiovascular system (Sommer and Fuqua, 2001) and its administration was associated with endometrial tumour development (Akhmedkhanov et al, 2001;Graziani et al, 2003).…”

“…These models have been widely used to test in vitro differentiation activity of agents like Na-butyrate and hexamethylene bisacetamide (HMBA) (Guilbaud et al, 1990), and retinoids including ATRA (Wang et al, 2001). More recently, emphasis was given to histone deacetylase inhibitors (HDACi) such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) which induce differentiation in breast cancer cells in vitro (Yang et al, 2000;Munster et al, 2001;Jang et al, 2004) by altering their transcriptional programs. However, the clinical use of HADCi including valproic acid to treat breast cancer is severely limited by the drug-mediated increase of ERa expression and tissue sensitization to tumour promotion activity of oestrogens (Akhmedkhanov et al, 2001;Graziani et al, 2003).…”

Histone Deacetylase Inhibitors for Cancer Therapy

“…99 Similarly, TSA treatment sensitized ER-negative breast cancer cells to anti-estrogen therapy by inducing ER-β expression. 100 Cell proliferation signaling pathways, mediated by tyrosine kinases, are one of the key targets for cancer therapy. HDACIs deplete several oncoproteins, such as Bcr-Abl and ErbB2, via hyperacetylation of the non-histone protein HSP90 which in turn promotes proteasomal degradation of Bcr-Abl and ErbB2 [58][59][60] (Fig.…”

Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential?

“…Interestingly, this appeared to be by inducing the expression and nuclear translocation of ERb but not ERa. Reduction of ERb expression by short interfering RNA abrogated this HDI-induced sensitisation effect (Jang et al, 2004). Evidence exists to suggest that DNA methylation and histone deacetylation interact to maintain a repressive chromatin complex at the ER promoter.…”