HDAC3 regulates stability of estrogen receptor α mRNA

ArticleinBiochemical and Biophysical Research Communications 432(2) · February 2013with15 Reads
DOI: 10.1016/j.bbrc.2013.02.007 · Source: PubMed
Abstract
Estrogen receptor alpha (ERα) expression is a risk factor for breast cancer. HDAC inhibitors have been demonstrated to down-regulate ERα expression in ERα-positive breast cancer cell lines, but the molecular mechanisms are poorly understood. Here, we showed that HDAC inhibitors decrease the stability of ERα mRNA, and that knockdown of HDAC3 decreases the stability of ERα mRNA and suppresses estrogen-dependent proliferation of ERα-positive MCF-7 breast cancer cells. In the Oncomine database, expression levels of HDAC3 in ERα-positive tumors are higher than those in ERα-negative tumors, thus suggesting that HDAC3 is necessary for ERα mRNA stability, and is involved in the estrogen-dependent proliferation of ERα-positive tumors.
    • "Recent findings indicate that immunohistochemical protein expression profiles are surrogates for intrinsic gene-derived expression profiles defining molecular breast cancer subtypes [8,9]. The biologic, prognostic and predictive importance of assessment of estrogen receptor (ER) expression in breast cancer is well established [10][11][12]. Gene expression profiling studies have shown that estrogen receptor (ER) -positive and ER-negative breast cancers are distinct diseases at the transcriptomic level [13]. Exposure to estrogen has been experimentally linked to the mutations that cause breast cancer. "
    [Show abstract] [Hide abstract] ABSTRACT: Abstract Background: Breast cancer is a major cause of morbidity and mortality worldwide. Immunohistochemical typing is important to understand the biological behavior of this disease. High mammographic density, which mostly attributed to collagen fibers, is among the strongest risk factors for developing breast cancer. Our objectives are to determine the type of connective tissue fibers in different breast lesions and to evaluate the relation between connective tissue fibers and estrogen expression. Methods: A total of 60 samples of breast lesions (35 were malignant and 25 were benign) was evaluated retrospectively. All specimens were diagnosed in the histopathology department of Laboratory Administration in Khartoum State, Sudan. The specimens were then re-examined for estrogen receptor status by immunohistochemistry and connective tissue fibers by Vangieson and Masson Trichrome (for collagen fibers), Silver stain (for reticular fibers) and Verhoeff (for elastic fibers) methods of staining. Findings: For the 35 malignant samples, immunohistochemical staining for estrogen receptors revealed positive expression in 12/35 (34.3%) and negative in 23/35 (65.7%) specimens. Benign samples showed 8/25 (32%) estrogen receptors positive and 17/25 (68%) estrogen receptors negative. Out of the total study subjects, there were 20/60 (33.3%) estrogen receptors positive. Interpretation: A significant correlation between estrogen receptors positive and presence of collagenic fibers (P-value = 0.000) was noticed. Furthermore, Elastic fibers were significantly associated with estrogen receptors positive (P-value = 0.039), as well as, Reticulin fibers (P-value = 0.020). Conclusion: The significant positive association between ER expression and all three types of connective tissue fibers suggests an underlying molecular relation and that the estrogen receptors expression might be predicted using histochemical demonstration as screening step for tissue biopsy. To the best of our knowledge, no study investigated the association between estrogen receptors and connective tissue fibers. Keywords: Breast cancer; Connective tissue; Immunohistochemistry; Estrogen receptor; Tissue fibers; Extracellular matrix; Mammographic density; Protein expression
    Full-text · Article · Jul 2016 · Clinical Breast Cancer
    • "We demonstrate that the HDAC inhibitor , PCI, efficiently reduces ER mRNA and protein in ER-positive TAMR M cells. We speculate this reduction is through similar mechanisms reported by other groups including pan-HDAC inhibitor-mediated induction of transcriptional repressor proteins, local methylation of CpG islands, influence on ER mRNA stability or through Hsp90 hyperacetylation resulting in loss of ER protein stability [40][41][42]. To the contrary, HDAC inhibition in ER-negative breast cancer cells, however, induces ER expression either through reversal of promoter hypermethylation or de-repression of ER mRNA via hyperactivated MAPK [43,44]. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: The emergence of hormone therapy resistance, despite continued expression of the estrogen receptor (ER), is a major challenge to curing breast cancer. Recent clinical studies suggest that epigenetic modulation by histone deacetylase (HDAC) inhibitors reverses hormone therapy resistance. However, little is known about epigenetic modulation of the ER during acquired hormone resistance. Our recent phase II study demonstrated that HDAC inhibitors re-sensitize hormone therapy-resistant tumors to the anti-estrogen tamoxifen. In this study, we sought to understand the mechanism behind the efficacy of this combination.
    Full-text · Article · Dec 2015
    • "We demonstrate that the HDAC inhibitor , PCI, efficiently reduces ER mRNA and protein in ER-positive TAMR M cells. We speculate this reduction is through similar mechanisms reported by other groups including pan-HDAC inhibitor-mediated induction of transcriptional repressor proteins, local methylation of CpG islands, influence on ER mRNA stability or through Hsp90 hyperacetylation resulting in loss of ER protein stability404142. To the contrary, HDAC inhibition in ER-negative breast cancer cells, however, induces ER expression either through reversal of promoter hypermethylation or de-repression of ER mRNA via hyperactivated MAPK [43,44]. "
    [Show abstract] [Hide abstract] ABSTRACT: The emergence of hormone therapy resistance, despite continued expression of the estrogen receptor (ER), is a major challenge to curing breast cancer. Recent clinical studies suggest that epigenetic modulation by histone deacetylase (HDAC) inhibitors reverses hormone therapy resistance. However, little is known about epigenetic modulation of the ER during acquired hormone resistance. Our recent phase II study demonstrated that HDAC inhibitors re-sensitize hormone therapy resistant tumors to the anti-estrogen tamoxifen. In this study, we sought to understand the mechanism behind the efficacy of this combination. We generated cell lines resistant to tamoxifen, named TAMR(M) and TAMR(T) by continuous exposure of ER positive MCF7 and T47D cells, respectively to 4-hydroxy tamoxifen for over 12 months. HDAC inhibition, along with pharmacological and genetic manipulation of key survival pathways, including ER and Bcl-2, were used to characterize these resistant models. The TAMR(M) cells displayed decreased sensitivity to tamoxifen, fulvestrant and estrogen deprivation. Consistent with previous models, ER expression was retained and the gene harbored no mutations. Compared to parental MCF7 cells, ER expression in TAMR(M) was elevated, while progesterone receptor (PR) was lost. Sensitivity of ER to ligands was greatly reduced and classic ER response genes were suppressed. This model conveyed tamoxifen resistance through transcriptional up regulation of Bcl-2 and c-Myc, and down regulation of the cell cycle checkpoint protein p21, manifesting in accelerated growth and reduced cell death. Similar to TAMR(M) cells, the TAMR(T) cell line exhibited substantially decreased tamoxifen sensitivity, increased ER and Bcl-2 expression and significantly reduced PR expression. Treatment with HDAC inhibitors reversed the altered transcriptional events and reestablished the sensitivity of the ER to tamoxifen resulting in substantial Bcl-2 down regulation, growth arrest and apoptosis. Selective inhibition of Bcl-2 mirrored these effects in presence of an HDAC inhibitor. Our model implicates elevated ER and Bcl-2 as key drivers of anti-estrogen resistance, which can be reversed by epigenetic modulation through HDAC inhibition.
    Full-text · Article · Dec 2015
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