Reported December 19, 2012
Putting the “Squeeze” on Breast Cancer

(Ivanhoe Newswire) – About 226,870 new cases of invasive breast cancer
in women will be diagnosed every year. Researchers have put the
squeeze — literally — on malignant mammary cells to guide them back
into a normal growth pattern.

The findings show for the first time that mechanical forces alone can
revert and stop the out-of-control growth of cancer cells. This change
happens even though the genetic mutations responsible for malignancy
remain, setting up a nature-versus-nurture battle in determining a
cell's fate.

"We are showing that tissue organization is sensitive to mechanical
inputs from the environment at the beginning stages of growth and
development," principal investigator Daniel Fletcher, professor of
bioengineering at UC Berkeley and faculty scientist at the Berkeley
Lab was quoted saying.

"An early signal, in the form of compression, appears to get these
malignant cells back on the right track," Fletcher continued.

Throughout a woman's life, breast tissue grows, shrinks and shifts in
a highly organized way in response to changes in her reproductive
cycle. For instance, when forming acini, the berry-shaped structures
that secrete milk during lactation, healthy breast cells will rotate
as they form an organized structure. And, importantly, the cells stop
growing when they are supposed to.

One of the early hallmarks of breast cancer is the breakdown of this
normal growth pattern. Not only do cancer cells continue to grow
irregularly when they shouldn't, recent studies have shown that they
do not rotate coherently when forming acini.

While the traditional view of cancer development focuses on the
genetic mutations within the cell, Mina Bissell, Distinguished
Scientist at the Berkeley Lab, conducted pioneering experiments that
showed that a malignant cell is not doomed to become a tumor, but that
its fate is dependent on its interaction with the surrounding
microenvironment. Her experiments showed that manipulation of this
environment, through the introduction of biochemical inhibitors, could
tame mutated mammary cells into behaving normally.

The latest work from Fletcher's lab, in collaboration with Bissell's
lab, takes a major step forward by introducing the concept of
mechanical rather than chemical influences on cancer cell growth.
Gautham Venugopalan, a member of Fletcher's lab, conducted the new
experiments as part of his recently completed Ph.D. dissertation at UC

"People have known for centuries that physical force can influence our
bodies," Venugopalan was quoted saying.

"When we lift weights, our muscles get bigger. The force of gravity is
essential to keeping our bones strong. Here we show that physical
force can play a role in the growth — and reversion — of cancer
cells," Venugopalan continued.

Venugopalan and collaborators grew malignant breast epithelial cells
in a gelatin-like substance that had been injected into flexible
silicone chambers. The flexible chambers allowed the researchers to
apply a compressive force in the first stages of cell development.

Over time, the compressed malignant cells grew into more organized,
healthy-looking acini that resembled normal structures, compared with
malignant cells that were not compressed. The researchers used time-
lapse microscopy over several days to show that early compression also
induced coherent rotation in the malignant cells, a characteristic
feature of normal development.

Notably, those cells stopped growing once the breast tissue structure
was formed, even though the compressive force had been removed.

"Malignant cells have not completely forgotten how to be healthy; they
just need the right cues to guide them back into a healthy growth
pattern," said Venugopalan.

Researchers further added a drug that blocked E-cadherin, a protein
that helps cells adhere to their neighbors. When they did this, the
malignant cells returned to their disorganized, cancerous appearance,
negating the effects of compression and demonstrating the importance
of cell-to-cell communication in organized structure formation.

It should be noted that the researchers are not proposing the
development of compression bras as a treatment for breast cancer.
"Compression, in and of itself, is not likely to be a therapy," said
Fletcher. "But this does give us new clues to track down the molecules
and structures that could eventually be targeted for therapies."

Source: The annual meeting of the American Society for Cell Biology in
San Francisco, December 2012

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