Study Finds HER2-positive
Breast Cancer Invades Organs Due To Fatal Chemical Attraction
Behind the Cancer Headlines®
Researchers at The University of Texas M. D. Anderson Cancer
Center have solved the mystery of why an aggressive form of HER2-positive
breast cancer travels readily to a few key organs - lungs, liver and bone -
where it then establishes new tumors. They say this finding may lead to
strategies to block that deadly spread.
The study, published in the journal Cancer Cell, describes a lethal attraction between signals found on HER2-positive
breast cancer cells and those on the surface of the organs - a magnetism that
explains why this form of breast cancer, which affects up to 30 percent of
patients, can be so invasive. The vast majority of women who die from
HER2-positive breast cancer had developed secondary tumors in their lung, liver
and bones.
"It has always been a puzzle as to why, when HER2-positive
cancer cells circulate throughout the body looking for a new home, they
preferentially travel to these organs," says the study's lead author, Mien-Chie
Hung, Ph.D., a professor and chair of the Department of Molecular &
Cellular Oncology. "We now have explained it
biochemically, and hope that this leads to
strategies that prevent such metastasis."
Their discovery focuses on the relationship between HER2 and
chemokine
receptor proteins on breast cancer cells.
Chemokines
are a large family of proteins primarily known to speed inflammatory responses
by drawing them to circulating white blood cells that have a corresponding
chemokine
receptor. Researchers have found that some diseases, including HIV and cancer,
use this same chemical attraction to invade the body.
Although scientists already had discovered that the
chemokine
receptor CXCR4 was involved in the movement of certain forms of breast cancer
to target organs, they did not know how CXCR4 did that for HER2-postive breast
cancer until now.
The M. D. Anderson team specifically found breast cancer that
overexpress
HER2 proteins also ramp up production of CXCR4. HER2-positive breast cancer
cells that float free of the tumor are studded with excess CXCR4 receptors,
which are previously known to be attracted to a
chemokine
produced by the target organs known as
stromal
cell-derived factor-1a, or SDF-1a. In other words, SDF-1a sends out a homing
signal to hundreds of CXCR4 receptors on HER2 breast cancer cells. This strong
attraction causes HER2-positive breast cancer cells to leave the blood and
lymphatic systems and migrate to organs with large amounts of these
chemokines, where the cancer cells then settle and
grow.
"HER2 turns on, and then magnifies, the ability of these
cancer cells to zero in on organs that release this chemical signal," says
Hung. "That explains why HER2 breast cancers can so easily induce metastasis."
The researchers specifically identified the pathway by which
HER2 switches on CXCR4 production. They then conducted a set of cell and animal
studies to test their findings. Examining human breast tumor tissues, they
found a significant correlation between HER2 and CXCR4 expression, and also
observed that CXCR4 expression was associated with a poor overall survival rate
in patients with breast cancer.
In lab and animal studies, Hung and his group then showed that
when they blocked CXCR4 expression in tumors by using a special RNA molecule,
the cancer became less invasive.
"Our data establish a molecular mechanism whereby
HER2-overexpressing cancer cells home in on specific organs and provide crucial
evidence of a functional link between the HER2 and CXCR4 signaling pathways,"
says Hung.
Clinically, the discovery may help physicians predict how
HER2-positive breast cancer will likely metastasize. The finding also "provides
strong support for the notion that an agent that can block CXCR4 could have
anticancer potential," says Hung. Efforts are now under way to develop such a
drug to treat cancer, he adds.
SOURCES:
Cancer Cell, November 2004
The University of Texas Health Science Center (http://www.mdanderson.org)