Epigenetic Therapy for Breast Cancer

Laboratory for Gynecological Oncology, Department of Biomedicine, Women's Hospital, University of Basel, Hebelstrasse 20, Room 420, Basel, CH 4031, Switzerland
International Journal of Molecular Sciences (Impact Factor: 2.86). 12/2011; 12(7):4465-87. DOI: 10.3390/ijms12074465
Source: PubMed


Both genetic and epigenetic alterations can control the progression of cancer. Genetic alterations are impossible to reverse, while epigenetic alterations are reversible. This advantage suggests that epigenetic modifications should be preferred in therapy applications. DNA methyltransferases and histone deacetylases have become the primary targets for studies in epigenetic therapy. Some DNA methylation inhibitors and histone deacetylation inhibitors are approved by the US Food and Drug Administration as anti-cancer drugs. Therefore, the uses of epigenetic targets are believed to have great potential as a lasting favorable approach in treating breast cancer.

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    • "Today, some DNMT and HDACs suppressors have been approved by Food and Drug Administration (FDA) as an anticancer treatment. The use of epigenetic targets is one of the promising ways for the treatment of cancer [71]. Azacitidine and decitabine were the first synthesized drugs for this purpose that suppress the DNMT enzyme. "
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    ABSTRACT: Epigenetic modifications can affect the long-term gene expression without any change in nucleotide sequence of the DNA. Epigenetic processes intervene in the cell differentiation, chromatin structure, and activity of genes since the embryonic period. However, disorders in genes' epigenetic pattern can affect the mechanisms such as cell division, apoptosis, and response to the environmental stimuli which may lead to the incidence of different diseases and cancers. Since epigenetic changes may return to their natural state, they could be used as important targets in the treatment of cancer and similar malignancies. The aim of this review is to assess the epigenetic changes in normal and cancerous cells, the causative factors, and epigenetic therapies and treatments.
    12/2013; 2013(21):317569. DOI:10.1155/2013/317569
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    • "VPA is an established and well-tolerated drug for epilepsy. It inhibits class I HDACs and also shows anti-tumour activity in a variety of human cancer cell lines including estrogen-sensitive and estrogen- insensitive breast cancer cell lines [40,41]. It is less toxic compared to TSA [42] and is in phase II and III clinical trials for many human cancers [43]. "
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    ABSTRACT: Background The behaviour of tumour cells depends on factors such as genetics and the tumour microenvironment. The latter plays a crucial role in normal mammary gland development and also in breast cancer initiation and progression. Breast cancer tissues tend to be highly desmoplastic and dense matrix as a pre-existing condition poses one of the highest risk factors for cancer development. However, matrix influence on tumour cell gene expression and behaviour such as cell migration is not fully elucidated. Results We generated high-density (HD) matrices that mimicked tumour collagen content of 20 mg/cm3 that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm3. Live-cell imaging showed breast cancer cells utilizing cytoplasmic streaming and cell body contractility for migration within HD matrix. Cell migration was blocked in the presence of both the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugs individually. This suggests roles for ROCK1 and MMP in cell migration are complicated by compensatory mechanisms. ROCK1 expression and protein activity, were significantly upregulated in HD matrix but these were blocked by treatment with a histone deacetylase (HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirect and relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA or DAPT abrogated the inhibition of ROCK1 by MS-275. Conclusion Increased matrix density elevates ROCK1 activity, which aids in cell migration via cell contractility. The upregulation of ROCK1 is epigenetically regulated in an indirect manner involving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1 expression.
    BMC Cell Biology 05/2012; 13(1):12. DOI:10.1186/1471-2121-13-12 · 2.34 Impact Factor
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    ABSTRACT: The histone deacetylase inhibitors, suberoylanilide hydroxamic acid (Vorinostat, Zolinza™) and depsipeptide (Romidepsin, Istodax™) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Numerous histone deacetylase inhibitors are currently undergoing clinical trials, predominantly in combination with other cancer modalities, for the treatment of various haematological and solid malignancies. Most of the traditional compounds are known as broad-spectrum or pan-histone deacetylase inhibitors, possessing activity against a number of the 11 metal-dependent enzymes. One of the main questions in the field is whether class- or isoform-specific compounds would offer a therapeutic benefit compared to broad-spectrum inhibitors. Therefore, analysis of the relative expression of the different histone deacetylase enzymes in cancer cells and tissues is important to determine whether there are specific targets. We used a panel of antibodies directed against the 11 known mammalian histone deacetylases to determine expression levels in MCF7 breast cancer cells and in tissue representative of invasive ductal cell carcinoma and ductal carcinoma in situ. Firstly, we utilized a semi-quantitative method based on immunofluorescence staining to examine expression of the different histone deacetylases in MCF7 cells. Our findings indicate high expression levels of HDAC1, 3 and 6 in accordance with findings from others using RT-PCR and immunoblotting. Following validation of our approach we examined the expression of the different isoforms in representative control and breast cancer tissue. In general, our findings indicate higher expression of class I histone deacetylases compared to class II enzymes in breast cancer tissue. Analysis of individual cancer cells in the same tissue indicated marked heterogeneity in the expression of most class I enzymes indicating potential complications with the use of class- or isoform-specific compounds. Overall, our approach can be utilized to rapidly compare, in an unbiased semi-quantitative manner, the differential levels of expression of histone deacetylase enzymes in cells and tissues using widely available imaging software. It is anticipated that such analysis will become increasingly important as class- or isoform-specific histone deacetylase inhibitors become more readily available.
    American Journal of Translational Research 01/2012; 4(1):24-43. · 3.40 Impact Factor
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