New cancer target: FOXR2 abnormally expressed in more than 70% of cancer types

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New cancer target: FOXR2 abnormally expressed in more than 70% of cancer types

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New cancer target: FOXR2 abnormally expressed in more than 70% of cancer types.

When Jessica Tsai, a pediatric oncologist at Dana-Farber Cancer Institute, was analyzing transcriptome sequences in pediatric brain cancer samples, she was surprised to find that many expressed Forkhead Box R2 (FOXR2), a gene on the X chromosome that is normally only expressed in the testes.

FOXR2 is part of a large family of highly conserved transcription factors that play a role in homeostasis and cellular stability. Scientists have identified FOXR2 as an oncogene in many cancers. However, the mechanism by which FOXR2 induces tumor formation remains unclear.

FOXR2 is aberrantly expressed in adult and childhood cancers through multiple mechanisms[1]

Jessica Tsai, along with pediatric neuroscientist Pratiti Bandopadhayay of the Broad Institute of MIT and Harvard, and a team led by Dana-Farber Cancer Institute, searched for Cancer Database, analyzed human cell cultures, and sequenced tumor genes in animal models to investigate why FOXR2 expression is increased in so many cancers.

After screening 10,000 adult and childhood cancer samples, the team found that FOXR2 is abnormally expressed in more than 70 percent of all cancer types, including adult melanoma, non-small cell lung cancer, childhood neuroblastoma and brain tumors.

The researchers also found that almost 80 percent of tumors expressing FOXR2 initiate transcription in a novel region of DNA called FOXR2 exon-3.

They found that the FOXR2 Exon-3 promoter was required for FOXR2 expression in cancer cells and was activated by hypomethylation of the X-chromosome region surrounding the FOXR2 gene.

The team next investigated which genes the FOXR2 transcription factor targets in cancer samples, and they found that FOXR2 binds to DNA sequences normally associated with E26 transformation-specific (ETS) transcription factors (ETS TFs), which control a variety of cellular functions expression of the gene.

“FOXR2 and the ETS TF can interact with DNA and actually turn genes on and off, leading to cancer,” said Timothy Phoenix, a pharmacy researcher at the University of Cincinnati and a co-author on the study.

Developing cancer treatments that inhibit FOXR2 expression is of interest to cancer researchers because it is not normally expressed in healthy cells.

While healthy testicular cells do express FOXR2, there is a unique barrier system, called the blood-testis barrier, that precludes potential FOXR2-targeting therapies.

Although researchers have a better understanding of FOXR2’s role in cancer, they still don’t know exactly how it works.

Timothy Phoenix and his team hope to identify specific proteins with which FOXR2 interacts, which will allow them to identify potential therapeutic targets.

references:

[1] Tsai, JW et al. FOXR2 is an epigenetically regulated pan-cancer oncogene that activates ETS transcriptional circuits. Cancer Res 82, 2980–3001 (2022).

[2] Liu, APY and Northcott, PA Pursuing FOXR2-driven oncogenesis. Cancer Res 82, 2977–2979 (2022).

New cancer target: FOXR2 abnormally expressed in more than 70% of cancer types

(source:internet, reference only)

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