BackgroundBRF2 is a transcription factor required for synthesis of a small group of non-coding RNAs by RNA polymerase III. Overexpression of BRF2 can transform human mammary epithelial cells. In both breast and lung cancers, the BRF2 gene is amplified and overexpressed and may serve as an oncogenic driver. Furthermore, elevated BRF2 can be independently prognostic of unfavorable survival. Dietary soy isoflavones increase metastasis to lungs in a model of breast cancer and a recent study reported significantly increased cell proliferation in breast cancer patients who used soy supplementation. The soy isoflavone daidzein is a major food-derived phytoestrogen that is structurally similar to estrogen. The putative estrogenic effect of soy raises concern that high consumption of soy foods by breast cancer patients may increase tumor growth.MethodsExpression of BRF2 RNA and protein was assayed in ER-positive or –negative human breast cancer cells after exposure to daidzein. We also measured mRNA stability, promoter methylation and response to the demethylating agent 5-azacytidine. In addition, expression was compared between mice fed diets enriched or deprived of isoflavones.ResultsWe demonstrate that the soy isoflavone daidzein specifically stimulates expression of BRF2 in ER-positive breast cancer cells, as well as the related factor BRF1. Induction is accompanied by increased levels of non-coding RNAs that are regulated by BRF2 and BRF1. Daidzein treatment stabilizes BRF2 and BRF1 mRNAs and selectively decreases methylation of the BRF2 promoter. Functional significance of demethylation is supported by induction of BRF2 by the methyltransferase inhibitor 5-azacytidine. None of these effects are observed in an ER-negative breast cancer line, when tested in parallel with ER-positive breast cancer cells. In vivo relevance is suggested by the significantly elevated levels of BRF2 mRNA detected in female mice fed a high-isoflavone commercial diet. In striking contrast, BRF2 and BRF1 mRNA levels are suppressed in matched male mice fed the same isoflavone-enriched diet.ConclusionsThe BRF2 gene that is implicated in cancer can be induced in human breast cancer cells by the isoflavone daidzein, through promoter demethylation and/or mRNA stabilization. Dietary isoflavones may also induce BRF2 in female mice, whereas the converse occurs in males.

Background Deregulation of the RNA polymerase III specific TFIIIB subunit BRF2 occurs in subtypes of human cancers. However, correlations between BRF2 alterations and clinical outcomes in breast cancer are limited. We conducted this review to analyze BRF2 alterations in genomic data sets housed in Oncomine and cBioPortal to identify potential correlations between BRF2 alterations and clinical outcomes. Methods The authors queried both Oncomine and cBioPortal for alterations in BRF2 in human cancers and performed meta-analyses identifying significant correlations between BRF2 and clinical outcomes in invasive breast cancer (IBC). Results A meta cancer outlier profile analysis (COPA) of 715 data sets (86,733 samples) in Oncomine identified BRF2 as overexpressed in 60% of breast cancer data sets. COPA scores in IBC data sets (3594 patients) are comparable for HER2 (24.211, median gene rank 60) and BRF2 (29.656, median gene rank 36.5). Overall survival in IBC patients with BRF2 alterations (21%) is significantly decreased (p = 9.332e-3). IBC patients with BRF2 alterations aged 46 to 50 have a significantly poor survival outcome (p = 7.093e-3). Strikingly, in metastatic breast cancer, BRF2 is altered in 33% of women aged 45–50. BRF2 deletions are predominant in this age group. Conclusion This study suggests BRF2 may be an prognostic biomarker in invasive breast carcinoma.

The RNA polymerase III–specific TFIIIB complex is targeted by oncogenes and tumor suppressors, specifically the TFIIIB subunits BRF1, BRF2, and TBP. Currently, it is unclear if the TFIIIB subunit BDP1 is universally deregulated in human cancers. We performed a meta-analysis of patient data in the Oncomine database to analyze BDP1 alterations in human cancers. Herein, we report a possible role for BDP1 in non-Hodgkin’s lymphoma (NHL) for the first time. To the best of our knowledge, this is the first study to report a statistically significant decrease in BDP1 expression in patients with anaplastic lymphoma kinase–positive (ALK+) anaplastic large-cell lymphoma (ALCL) (p = 1.67 × 10−6) and Burkitt’s lymphoma (BL) (p = 1.54 × 10−11). Analysis of the BDP1 promoter identified putative binding sites for MYC, BCL6, E2F4, and KLF4 transcription factors, which were previously demonstrated to be deregulated in lymphomas. MYC and BDP1 expression were inversely correlated in ALK+ ALCL, suggesting a possible mechanism for the significant and specific decrease in BDP1 expression. In activated B-cell (ABC) diffuse large B-cell lymphoma (DLBCL), decreased BDP1 expression correlated with clinical outcomes, including recurrence at 1 year (p = 0.021) and 3 years (p = 0.005). Mortality at 1 (p = 0.030) and 3 (p = 0.012) years correlated with decreased BDP1 expression in ABC DLBCL. Together, these data suggest that BDP1 alterations may be of clinical significance in specific NHL subtypes and warrant further investigation.

TFIIIB is deregulated in a variety of cancers. However, few studies investigate the TFIIIB subunit BDP1 in cancer. BDP1 has not been studied in breast cancer patients. Herein, we analyzed clinical breast cancer datasets to determine if BDP1 alterations correlate with clinical outcomes. BDP1 copy number (n = 1602; p = 8.03 × 10−9) and mRNA expression (n = 130; p = 0.002) are specifically decreased in patients with invasive ductal carcinoma (IDC). In IDC, BDP1 copy number negatively correlates with high grade (n = 1992; p = 2.62 × 10−19) and advanced stage (n = 1992; p = 0.005). BDP1 mRNA expression also negatively correlated with high grade (n = 55; p = 6.81 × 10−4) and advanced stage (n = 593; p = 4.66 × 10−4) IDC. Decreased BDP1 expression correlated with poor clinical outcomes (n = 295 samples): a metastatic event at three years (p = 7.79 × 10−7) and cancer reoccurrence at three years (p = 4.81 × 10−7) in IDC. Decreased BDP1 mRNA correlates with patient death at three (p = 9.90 × 10−6) and five (p = 1.02 × 10−6) years. Both BDP1 copy number (n = 3785; p = 1.0 × 10−14) and mRNA expression (n = 2434; p = 5.23 × 10−6) are altered in triple-negative invasive breast cancer (TNBC). Together, these data suggest a role for BDP1 as potential biomarker in breast cancer and additional studies are warranted.

High-risk human papillomaviruses (HPV) are important agents, responsible for a large percentage of the 745,000 cases of head and neck squamous cell carcinomas (HNSCC), which were identified worldwide in 2020. In addition to being virally induced, tobacco and heavy alcohol consumption are believed to cause DNA damage contributing to the high number of HNSCC cases. Gene expression and DNA methylation differ between HNSCC based on HPV status. We used publicly available gene expression and DNA methylation profiles from the Cancer Genome Atlas and compared HPV positive and HPV negative HNSCC groups. We used differential gene expression analysis, differential methylation analysis, and a combination of these two analyses to identify the differences. Differential expression analysis identified 1854 differentially expressed genes, including PCNA, TNFRSF14, TRAF1, TRAF2, BCL2, and BIRC3. SYCP2 was identified as one of the top deregulated genes in the differential methylation analysis and in the combined differential expression and methylation analyses. Additionally, pathway and ontology analyses identified the extracellular matrix and receptor interaction pathway as the most altered between HPV negative and HPV positive HNSCC groups. Combining gene expression and DNA methylation can help in elucidating the genes involved in HPV positive HNSCC tumorigenesis, such as SYCP2 and TAF7L.