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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 long associated with brain development: orchestrating the growth of mammary glands during puberty. The findings may have important implications for the development 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: L. Hinck

The molecule, a signaling protein called netrin-1, has been intensively studied for its role in guiding the growth of nerve cells. The UCSC researchers, led by assistant professor of molecular, cell and developmental 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 about netrin-1 in the nervous system, but no one had a clue about what it did outside 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 done breast cancer research in another lab. Undergraduate students Ana Valdes and Grace Shin also helped with the research. The group's findings appeared 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, the researchers 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 coin.

"In the nervous system netrin-1 functions as a long-range cue to establish neural connections, and in the mammary gland netrin-1 acts as a short-range cue to assemble cells into an organized structure," she said.

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 glands have 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 for netrin-1 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 development," said Srinivasan.

Both the netrin-1 and the neogenin knockouts displayed breaks in the basal lamina, the membrane surrounding the end bud of the mammary gland. 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 also investigating the roles of other signaling molecules in the mammary gland.


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