Transcription Factor That Determines Breast Cancer Subtypes Identified

Cancer researchers in Australia have identified a transcription factor that is largely responsible for establishing the intrinsic patterns of gene expression that characterize the various molecular subtypes of breast cancer and can be used to group patients with different prognoses and treatment options.

The factor under study is ELF5, a member of the ETS family of transcription factors, which is present throughout the body and is involved in a wide variety of functions including the regulation of cellular differentiation, cell cycle control, cell migration, cell proliferation, apoptosis, and angiogenesis.

Investigators at the Garvan Institute of Medical Research (Sydney, Australia) had previously reported that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directed the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers.

To test this theory they constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq).

Results published in the December 27, 2012, online edition of the journal PLOS Biology revealed that ELF5 was responsible for much of the patterning of gene expression that distinguished breast cancer subtypes. Additionally, ELF5 seemed to be involved in the development of resistance to therapies designed to stop estrogen stimulation of breast cancer. These effects of ELF5 may represent a partial carryover into breast cancer of its normal role in the mammary gland, where it is responsible for the development of milk-producing structures during pregnancy.

"This work tells us that cancers which become refractory to antiestrogen treatment often do so by elevating their levels of ELF5 and becoming functionally estrogen receptor negative," said senior author Dr. Christopher Ormandy, associate professor of cancer research at the Garvan Institute of Medical Research.

By manipulating ELF5 levels in cancer cells in the laboratory, the investigators showed that it was possible to alter the subtype of breast cancer. "This raises the therapeutic option of manipulating ELF5 levels to treat breast cancer," said Dr. Ormandy. "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. Our key discovery here is that by simply manipulating one transcription factor we can change the subtype of breast cancer."

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Garvan Institute of Medical Research