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A Transcription Factor May Influence the Molecular Subtype of Breast Cancer

NEW YORK (GenomeWeb News) – A transcription factor called ELF5 may be a main determinant of breast cancer type, a team of Australian researchers reported in PLOS Biology last night. In addition, they reported that by changing ELF5 levels, they could manipulate, in the lab, cancer subtype.

A number of tests to distinguish, and drugs tailored to, cancer subtypes are making their way to the clinic, and the researchers said that having a better understanding of how such subtypes arise could lead to better predictive markers or new therapies for cancer.

"Our key discovery here is that by simply manipulating one transcription factor we can change the subtype of breast cancer," said senior author Christopher Ormandy from the Garvan Institute of Medical Research in a statement.

In a 2008 Genes and Development paper, Ormandy and his colleagues determined that, during pregnancy, ELF5 guides the development of breast cells into milk-producing, estrogen-receptor negative cells. Now in cancer cells, they suspect that that function may be subverted.

To work out how ELF5 affects gene expression patterns, the researchers developed inducible models of ELF expression in estrogen receptor-positive luminal breast cancer cells, which they then subjected to transcript profiling and ChIP-seq analysis. From this, they found that ELF5 suppressed ER and FOXA1 expression. As both of those are involved in determining ER-positive luminal breast cancer subtypes, their suppression also led to the suppression of genes linked to the luminal breast cancer subtype.

Additionally, the researchers reported that FOXA1, EGFR, and MYC are among ELF5's direct transcriptional targets.

"ELF5 exerts wide transcriptional effects with functional outcomes on cell proliferation, adhesion, the molecular determinants of breast cancer subtype and phenotype, and acquired resistance to tamoxifen," Ormandy and his colleagues write. "These outcomes are aspects of a general specification of an estrogen-insensitive cell fate exerted through modulation of ER, FOXA1, and other transcriptional regulators in luminal cells, and the induction of basal characteristics in basal cells."

Knocking ELF5 down in basal breast cancer cell lines, they added, led to changes in gene expression patterns and shifted the molecular subtypes of those basal cancer cell lines to resemble claudin-low and normal-like subtypes.

Meanwhile, the researchers showed that luminal breast cancer cells that are resistant to tamoxifen have higher levels of ELF5, indicating that ELF5 could be a therapeutic target for anti-estrogen-resistant cancer or a marker predicting anti-estrogen therapy failure.

"This raises the therapeutic option of manipulating ELF5 levels to treat breast cancer," Ormandy said. "As ELF5 is intracellular, this could possibly be done with small molecule therapies that penetrate cells and target protein-to-protein interactions, or with small inhibitory RNAs. There is also the possibility of testing ELF5 levels in tumors to predict response to treatment and therefore guide treatment decisions."

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