BUFFALO, N.Y. -- A protein that is necessary for lactation in
mammals inhibits the critical cellular transition that is an early
indicator of breast cancer and metastasis, according to research
conducted at the University at Buffalo and Princeton University and
highlighted as the cover paper in November issue of Nature Cell
"This is the first confirmed report that this protein, called
Elf5, is a tumor suppressor in breast cancer," explains Satrajit
Sinha, PhD, associate professor of biochemistry in the UB School of
Medicine and Biomedical Sciences and a corresponding author on the
paper with Yibin Kang, PhD, in the Department of Molecular Biology
at Princeton University.
The researchers say the findings provide new avenues to pursue
in treating and diagnosing breast cancer and possibly cancers of
other organs as well. The paper includes findings from both animal
and human breast cancer models.
Under normal circumstances, Elf5 is a transcription factor that
controls the genes that allow for milk production.
But when the researchers used knockout mice developed at UB, in
whom Elf5 was removed, they found more than just an inability to
produce milk. They found that epithelial cells in the mammary
glands also became more mesenchymal, that is, more like stem cells,
an early harbinger of cancer, Sinha says.
"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," says Sinha. "This is how cancer spreads."
The UB-Princeton collaboration began when lead author Rumela
Chakrabarti, PhD, originally a postdoctoral researcher in Sinha's
laboratory at UB, took a position in the laboratory of Yibin Kang,
PhD, Warner-Lambert/Parke-Davis Professor of Molecular Biology at
Princeton, whose research focus is breast cancer metastasis. This
allowed Chakrabarti to harness the expertise of the two
laboratories to generate such a breakthrough finding.
"Elf5 keeps normal breast cells in their current shape and
restricts their movement," says Chakrabarti. She found that the
protein accomplishes this by suppressing the epithelial-mesenchymal
transition by directly repressing transcription of Snail2, a master
regulator of mammary stem cells known to trigger the EMT.
"Elf5 keeps Snail2 repressed, but once Elf5 is lost, then there
is nothing to repress Snail 2," she explains.
The paper notes that Elf5 loss is frequently detected early in
the disease at the breast hyperplasia stage, when the number of
cells increases. In experiments conducted by the Princeton
scientists, the researchers also found that little or no Elf5 in
human breast cancer samples correlated with increased
"It seems that loss of Elf5 is an initial event in the disease,
so it could also be an important diagnostic tool," Sinha notes,
which is a current focus of the UB and Princeton team.
"We want to know, how early does the loss of Elf5 occur? Could
we use loss of Elf5 as a reliable diagnostic tool?" he asks.
The finding reveals the complex pathways through which breast
cancers develop, he says, while also providing new avenues to
pursue for diagnostics and treatments.
"Our research shows that the EMT-Snail 2 pathway is a valuable
one to target for early breast cancer intervention," says Sinha,
"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."
Other UB co-authors on the paper are Rose-Anne Romano, PhD,
research assistant professor in biochemistry, and Kirsten Smalley,
research technician. Other coauthors are: Julie Hwang, Mario Andres
Blanco, Martin Lukacisin and Yong Wei from Princeton; Song Liu of
Roswell Park Cancer Institute; Qifeng Yang and Bruce F. Haffty of
the Department of Radiation Oncology in the University of Medicine
and Dentistry of New Jersey and the Cancer Institute of New Jersey;
and Toni Ibrahim, Laura Mercatali and Dino Amadori of the Istituto
Scientifico Romagnolo per lo Studio e la Cura dei Tumori in
The research was supported by the National Institutes of Health,
the Department of Defense, Komen for the Cure, the Brewster
Foundation and the Champalimaud Foundation.