Lactation Protein Inhibits Tumors and Metastasis in Breast Cancer

The breakthrough finding is highlighted as the cover paper in the November issue of Nature Cell Biology.

“This is the first confirmed report that this protein, called Elf5, is a tumor suppressor in breast cancer,” says Satrajit Sinha, PhD, UB associate professor of biochemistry and corresponding author with Princeton’s Yibin Kang, PhD.

The research, which includes findings from animal and human breast cancer models, provides new avenues to pursue in treating and diagnosing breast cancer—and possibly cancers of other organs as well, researchers note.

Under normal circumstances, Elf5 is a transcription factor that controls the genes that allow for milk production.

But when UB researchers developed knockout mice in whom Elf5 was removed, the team found more than just an inability to produce milk:

Epithelial cells in the mammary glands also became more mesenchymal—an early harbinger of cancer.

“We found that when Elf5 levels are low or absent, epithelial cells become more like stem cells, morphing into mesenchymal cells, changing their shape and appearance and migrating elsewhere in the body,” Sinha says.

“This is how cancer spreads.”

During the research, lead author Rumela Chakrabarti, PhD, found that Elf5 suppresses the epithelial-mesenchymal transition (EMT) by directly repressing transcription of Snail2, a key regulator of mammary stem cells known to trigger EMT. This process keeps normal breast cells in their current shape and restricts their movement.

“Elf5 keeps Snail2 repressed, but once Elf5 is lost, there is nothing to repress Snail2,” Chakrabarti explains.

Elf5 loss is frequently detected early in the disease, at the breast hyperplasia stage, when the number of cells increases, the authors note.

In experiments conducted by the Princeton scientists, researchers also found that little or no Elf5 in human breast cancer samples correlates with increased morbidity.

“It seems that loss of Elf5 is an initial event in the disease, so it could also be an important diagnostic tool,” Sinha says.

The UB-Princeton team is currently focused on how early Elf5 loss occurs and whether it could serve as such a tool.

Their collaboration began when Chakrabarti, originally a postdoctoral researcher in Sinha’s laboratory, took a position researching breast cancer metastasis in the laboratory of Kang, Princeton’s Warner-Lambert/Parke-Davis Professor of Molecular Biology.

The team’s finding reveals the complex pathways through which breast cancers develop while providing new avenues to pursue diagnostics and treatments.

“Our research shows that the EMT-Snail2 pathway is a valuable one to target for early breast cancer intervention,” Sinha says, “possibly by designing something to recapture the repressive effect of Elf5 or a drug that could mimic Elf5 activity.

“And this is just one molecule, part of a big network. That’s why we are now creating a detailed map of this molecule and its associated partners in order to give us a better idea of what to look for.”

The team’s research was supported by the National Institutes of Health, the Department of Defense, Komen for the Cure, the Brewster Foundation and the Champalimaud Foundation.

Other UB co-authors on the paper are Rose-Anne Romano, PhD, research assistant professor in biochemistry, and Kirsten Smalley, research technician.

Co-authors from collaborating institutions are:

• Julie Hwang, Mario Andres Blanco, Martin Lukacisin and Yong Wei (Princeton)
• Song Liu (Roswell Park Comprehensive Cancer Center)
• Qifeng Yang and Bruce F. Haffty (Department of Radiation Oncology in the University of Medicine and Dentistry of New Jersey and the Cancer Institute of New Jersey)
• Toni Ibrahim, Laura Mercatali and Dino Amadori (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori)