Alcohol Intake and Abnormal Expression of Brf1 in Breast Cancer

Abstract

Breast cancer is the most common malignant disease of females. Overall, one woman in every nine will get breast cancer at some time in her life. Epidemiological studies have indicated that alcohol consumption has most consistently been associated with breast cancer risk. However, the mechanism of alcohol-associated breast cancer remains to be addressed. Little is known about the effects of alcohol consumption on Brf1 (TFIIIB-related factor 1) expression and RNA Pol III gene (RNA polymerase III-dependent gene) transcription, which are responsible for protein synthesis and tightly linked to cell proliferation, cell transformation, and tumor development. Emerging evidences have indicated that alcohol induces deregulation of Brf1 and Pol III genes to cause the alterations of cell phenotypes and tumor formation. In this paper, we summarize the progresses regarding alcohol-caused increase in the expression of Brf1 and Pol III genes and analysis of its molecular mechanism of breast cancer. As the earlier and accurate diagnosis approach of breast cancer is not available yet, exploring the molecular mechanism and identifying the biomarker of alcohol-associated breast cancer are especially important. Recent studies have demonstrated that Brf1 is overexpressed in most ER+ (estrogen receptor positive) cases of breast cancer and the change in cellular levels of Brf1 reflects the therapeutic efficacy and prognosis of this disease. It suggests that Brf1 may be a potential diagnosis biomarker and a therapeutic target of alcohol-associated breast cancer.

Figure 1

The alteration of the TFIIIB complex of transcription machinery. TFIIIB is a complex of the transcription machinery of RNA Pol III genes; TFIIIB includes Brf1, Bdp1, and TBP. Oncogenic proteins, such as c-Jun, c-Myc, Ras, and c-Fos activate TFIIIB to enhance RNA Pol III gene transcription, resulting in tumorigenesis. In contrast, tumor suppressors, such as BRCA1, PTEN, p53, and pRb, inactivate its activity to decrease the transcription of Pol III genes, leading to repression of tumor development.

Figure 2

The alcohol-induced modulation of Brf1 expression. Alcohol increases Brf1 expression through two ways in breast cells. One is that alcohol activates JNK1 and MSK1 to upregulate Brf1 expression; another way is that alcohol activates JNK1 to enhance ERα and Runx2 expression, leading to augmenting Brf1 expression. The two pathways increase RNA Pol III gene, eventually resulting in cell proliferation and transformation and mammary tumor development, while Tam inhibits ERα activity and decreases the cellular level of Brf1.

Figure 3

Alcohol-induced histone H3 phosphorylation which upregulates Brf1 expression. Alcohol induces activation of MSK1, which binds to the sites of chromatin of the target genes. Activated MSK1 mediates histone H3 phosphorylation (H3ph) to cause chromatin remodeling at local, leading to increases in Brf1 transcription. P: the phosphorylation group.