**2.2.3 Histone phosphorylation in breast cancer**

Phosphorylation is also thought to have a role in chromatin remodeling and in the initiation of gene transcription, and therefore be associated with the development of human cancer (Espino et al., 2006; Wang et al., 2007). Phosphorylation of H3 on S10 and S28 is important not only during mitotic chromosome condensation but also in transcriptional activation of immediate early genes. The number of H3 pS10 foci was increased, and these TPA-induced foci were positioned next to actively transcribed regions in the nucleus after TPA stimulating of MCF-7 breast cancer cells. Presumably, these nuclear sites represent the nuclear location of genes that are induced or in a competent state. Thus, growth factors stimulating the Ras/MAPK and increasing H3 pS10 at transcriptionally active loci may contribute to aberrant gene expression and breast cancer progression (Espino et al., 2006).

#### **2.2.4 The other histone modifications in breast cancer**

Besides the acetylation, methylation and phosphorylation, there are some other modification occurred in the histone. These epigenetic changes include ubiquitination/sumoylation, ADP-ribosylation, deamination, and proline isomerisation. Although the knowledge of their functions and mechanisms is still little, some studies have showed that they are also associated with breast cancer and other human cancers.

The regulation of gene expression by phosphorylated and undersumoylated PRs is a novel form of hormone independent PR action that is predicted to contribute to breast cancer cell growth and survival (Daniel et al., 2009). Recent studies revealed that E3 ubiquitin ligases play important roles in breast carcinogenesis. ubiquitin-mediated protein degradation plays an important role in many cancer-related cellular processes. E3s play critical roles because they control the substrate specificity. Accumulating evidence suggests that genetic and expression alteration of E3s contributes to breast carcinogenesis (Chen et al., 2006).

histone sumoylation as a component of the group of modifications that appear to govern chromatin structure and function to mediate transcriptional repression and gene silencing (Shiio et al., 2003). A better understanding of the epigenetic mechanisms that cause transcriptional repression has allowed researchers to find new agents that are very effective in inducing apoptosis , differentiation, and/or cell growth arrest in human breast cancer, lung cancer, thoracic cancer, leukemia, and colon cancer cell lines (Giacinti et al., 2006).

### **2.3 Histone modification inhibitors and breast cancer**

As discussed above, histone modification could be used as a novel target for the research of anticancer drugs. So far, several histone modification inhibitors have been developed. HDAC inhibitors are the most studied type of histone modification inhibitor up to now (Tab 3).

It showed that combination of the HDAC inhibitor vorinostat with paclitaxel and bevacizumab could induce a partial or complete response in more than 50% of patients with metastatic breast cancer (Wong, 2009; Jovanovic et al., 2010). In addition, the HDAC inhibitors have different role in ER+ and ER- breast cancer cells. In ER+ cells, HDAC inhibitors reduce the transcriptional level of ER and its response genes, while they

et al., 2007). LSD1 might be a coactivator in the ER signalling (Garcia-Bassets et al., 2007). JMJD1C expression is decreased in breast cancer tissues compared with normal breast

Phosphorylation is also thought to have a role in chromatin remodeling and in the initiation of gene transcription, and therefore be associated with the development of human cancer (Espino et al., 2006; Wang et al., 2007). Phosphorylation of H3 on S10 and S28 is important not only during mitotic chromosome condensation but also in transcriptional activation of immediate early genes. The number of H3 pS10 foci was increased, and these TPA-induced foci were positioned next to actively transcribed regions in the nucleus after TPA stimulating of MCF-7 breast cancer cells. Presumably, these nuclear sites represent the nuclear location of genes that are induced or in a competent state. Thus, growth factors stimulating the Ras/MAPK and increasing H3 pS10 at transcriptionally active loci may contribute to aberrant gene expression and breast cancer progression (Espino et al., 2006).

Besides the acetylation, methylation and phosphorylation, there are some other modification occurred in the histone. These epigenetic changes include ubiquitination/sumoylation, ADP-ribosylation, deamination, and proline isomerisation. Although the knowledge of their functions and mechanisms is still little, some studies have showed that they are also

The regulation of gene expression by phosphorylated and undersumoylated PRs is a novel form of hormone independent PR action that is predicted to contribute to breast cancer cell growth and survival (Daniel et al., 2009). Recent studies revealed that E3 ubiquitin ligases play important roles in breast carcinogenesis. ubiquitin-mediated protein degradation plays an important role in many cancer-related cellular processes. E3s play critical roles because they control the substrate specificity. Accumulating evidence suggests that genetic and

histone sumoylation as a component of the group of modifications that appear to govern chromatin structure and function to mediate transcriptional repression and gene silencing (Shiio et al., 2003). A better understanding of the epigenetic mechanisms that cause transcriptional repression has allowed researchers to find new agents that are very effective in inducing apoptosis , differentiation, and/or cell growth arrest in human breast cancer, lung cancer, thoracic cancer, leukemia, and colon cancer cell lines (Giacinti et al., 2006).

As discussed above, histone modification could be used as a novel target for the research of anticancer drugs. So far, several histone modification inhibitors have been developed. HDAC inhibitors are the most studied type of histone modification inhibitor up to now (Tab

It showed that combination of the HDAC inhibitor vorinostat with paclitaxel and bevacizumab could induce a partial or complete response in more than 50% of patients with metastatic breast cancer (Wong, 2009; Jovanovic et al., 2010). In addition, the HDAC inhibitors have different role in ER+ and ER- breast cancer cells. In ER+ cells, HDAC inhibitors reduce the transcriptional level of ER and its response genes, while they

expression alteration of E3s contributes to breast carcinogenesis (Chen et al., 2006).

tissues, indicating that it might be a tumor suppressor (Wolf et al., 2007).

**2.2.3 Histone phosphorylation in breast cancer** 

**2.2.4 The other histone modifications in breast cancer** 

associated with breast cancer and other human cancers.

**2.3 Histone modification inhibitors and breast cancer** 

3).

reestablish ER expression in ER- cell lines. But the HDAC inhibitor could potentiate and restore the efficacy of anti-estrogen therapy in preclinical models in either ER+ or ER- breast cancer cells. This has led to the initiation of several clinical trials combining HDAC inhibitors with anti-estrogen therapy (Thomas et al., 2009). LAQ824 is a novel inhibitor of HDAC that shows antineoplastic activity and can activate genes that produce cell cycle arrest. Combination of the LAQ824 and a DNMT inhibitor (decitabine) showed a synergistic (re-)activation of silenced tumor-suppressor genes in human MDA-MB-231 and MCF-7 breast carcinoma cells (Hurtubise et al., 2006).


TPX

AOE

Histone Modification and Breast Cancer 335

the development of novel anticancer strategies. The understanding of all these epigenetics changes and their contribution to breast cancer might take great progress in the eld of

This work was financially supported by the National Basic Research Program of China (973 Program) (NO. 2009CB825504), the National Natural Science Fundation of China (NO. 31000343), the High School Science & Technology Development Fundation of Tianjin (NO.20090602) and the Scientific Research Launch Fund for Introduction of Talents into

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**5. References** 

917-32.

711-21.


Table 3. Summary of major HDAC inhibitors (Acharya et al., 2005; Laird, 2005).
