May 12, 2003
New role for brain chemical found in mammary
glands, with implications for breast cancer research
By Shawna Williams
UCSC researchers have discovered a new role for a molecule
with brain development: orchestrating the growth of mammary
puberty. The findings may have important implications for
of breast cancer.
|In developing mammary glands,
orderly cell layers form in a normal end bud (top), but loss of
netrin-1 results in abnormal growth (above). Photo:
The molecule, a signaling protein called netrin-1, has
studied for its role in guiding the growth of nerve cells. The UCSC
researchers, led by assistant professor of molecular, cell
biology Lindsay Hinck, are the first to show a function for netrin-1
outside the nervous system.
"This was a really new concept because everybody knew
in the nervous system, but no one had a clue about what it
the nervous system," said Karpagam "Shalu" Srinivasan,
a graduate student who helped make the discovery.
For nine years, Hinck has studied the role of netrin-1 in directing
the development of the embryonic nervous system. Netrins are one of
four major families of molecular signals that guide growing nerve cells
to their targets, ultimately producing the elaborate network of connections
that makes up the nervous system.
When netrins connect with specific receptors on a nerve cell's surface,
they prompt changes in the cell that cause it to grow toward or away
from the area where netrins are concentrated.
But other researchers had found netrin-1 in different
tissues, as well,
suggesting additional roles for the molecule.
"About two and a half years ago I decided to start a whole new
direction in the lab," Hinck said.
She decided to figure out what netrin-1 does in mammary tissue, one
of the places where it had been detected. Both Hinck and Srinivasan
had studied the nervous system, and the new project
combined their expertise
with that of research assistant Phyllis Strickland, who had
cancer research in another lab. Undergraduate students Ana Valdes and
Grace Shin also helped with the research. The group's
in the March issue of the journal Developmental Cell.
During puberty, the mammary gland grows into the fat pad, led by the
vigorous growth and branching of the gland's tips, called end buds.
"During puberty, these end buds are just plowing along at half
a millimeter a day into the fat pad," Hinck said.
Hinck's group theorized that netrin-1 might guide the buds
in the same
way it guides nerve cells in the embryonic brain. Instead,
found that it functions as a kind of glue, holding the cells of the
end bud together.
Getting end bud cells to stick together in the breast may seem quite
different from guiding brain cells toward or away from a target, but
Hinck sees the two functions as different sides of the same
"In the nervous system netrin-1 functions as a long-range cue
to establish neural connections, and in the mammary gland
as a short-range cue to assemble cells into an organized
Hinck's lab examined the effects of netrin-1 in mice. To study the
role of a protein in a model organism, researchers usually "knock
out" the gene that codes for that protein and see what happens.
Hinck's group compared the development of mammary glands
with and without
the netrin-1 gene.
Both the normal and the knockout glands grew in a way that appeared
normal at first look. But where end buds of normal mammary
tightly adhering layers of cells, each with its own
function, the cell
layers in the knockout buds were widely spaced and disorganized.
The researchers observed the same effect when they knocked out the
gene for neogenin, a known receptor for netrin-1 in the brain. This
is strong evidence that neogenin is acting as the receptor
in the mammary gland. As with netrin-1, Hinck's group was the first
to discover a function for neogenin outside the nervous system.
"Our studies showed for the first time that without neogenin,
you can see something going wrong with early mammary gland
Both the netrin-1 and the neogenin knockouts displayed breaks in the
basal lamina, the membrane surrounding the end bud of the
When tumors develop, an intact basal lamina is essential to contain
the tumor cells and prevent metastasis of the cancer.
Because of this,
Hinck believes mutations in the genes for netrin-1 or neogenin may be
associated with invasive breast cancer.
The group plans to test samples of human tumors to see whether their
netrin-1 or neogenin genes have mutations. Hinck's lab is
the roles of other signaling molecules in the mammary gland.
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