A protein that plays a key role in lactation could also represent a diagnostic biomarker and therapeutic target for breast cancer, scientists claim. The protein, Elf5, is a member of the E twenty-six family of transcription factors, several of which have previously been implicated in cancer initiation, progression, and metastasis.

Elf5 itself is a key regulator of cell fate determination in the mammary gland. A State University of New York at Buffalo, and Princeton University-led team has now carried out a series of in vitro and vivo studies that have shown how Elf5 also acts to suppress epithelial to mesenchymal transition (EMT) and cancer metastasis through direct transcriptional repression of Snail2 in both the mammary gland epithelium and in breast cancer. Snail2 is a master regulator of mammary stem cells and a known inducer of EMT.

Their work in rodents with Elf5-knockout (KO) mammary glands showed that lack of the transcription factor leads to gene expression changes associated with several molecular features of EMT. And when they stably overexpressed Elf5 in normal murine mammary gland (NMuMG) epithelial cells, the cells were able to resist undergoing EMT in response to the addition of TGF-β, which normally triggers EMT in epithelial cells.

Supporting a role for Elf5 in suppressing EMT, the researchers also found Elf5 gene expression was much lower in breast cancer cell lines characterized by mesenchymal morphology and high metastatic potential. And knocking down Elf5 in a breast cancer cell line that normally exhibits moderate basal levels of Elf5 induced EMT-like features. Conversely, when a highly metastatic, mesenchymal-like breast cancer cell line was forced to overexpress Elf5, the cells underwent the reverse, mesenchymal-to-epithelial process, effectively reverting back into an epithelial state.

Subsequent in vitro studies showed that Elf5 suppresses the EMT-related transcription factor Snail2, and when the investigators looked more closely at microarray datasets from clinical samples they found both that Elf5 expression was markedly reduced in hyperplasia and multiple breast tumor subtypes, and that there was an inverse correlation between the expression of Elf5 and the Snail2 gene, Snai2. Interestingly, analysis of microarray data also found a link between good prognosis and high levels of Elf5 expression, and poorer prognosis and high tumor Snai2 expression levels.

Moreover, direct evaluation of breast cancer samples by Princeton’s Yibin Kang, Ph.D., et al showed that Elf5 is lost during the early onset of breast cancer progression, at the stage of breast hyperplasia.

The team separately carried out a series of in vivo experiments to evaluate the effects of Elf5 on breast tumor metastasis to the lungs. The combined data from studies in xenograft and allograft metastasis models, as well as the MMTV-Neu transgenic mouse models, showed that tumors overexpressing Elf5 were far less able to metastasize, whereas Elf5-KO tumors more readily metastasized and generated increased numbers of lung metastasis nodules.

The researchers claim their studies provide the first confirmation that Elf5 acts as a tumor suppressor in breast cancer, and that the Elf5-Snail2 pathway could represent a promising target for intervention in early breast cancer. And, they add, because the loss of Elf5 occurs as an initial event in the disease, measuring levels of the transcription factor could also represent a useful diagnostic tool.

“Together, our analyses have concluded that Elf5, through its direct negative regulation of Snail2, serves as a master enforcer of the epithelial cell fate,” the team writes in a paper in Nature Cell Biology. “In the physiological context, this role promotes the proper identity of alveolar mammary epithelial cells, whereas in the pathological context Elf5 functions as a suppressor of EMT and cancer metastasis.”

The published paper is titled “Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2.”

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