Researchers have identified a protein long known to regulate
gene expression as a potent suppressor of breast cancer growth. Their study, in
Oncogene, is the first to demonstrate
how this protein, known as Runx3, accomplishes this feat.
“People suggested that Runx3 might be a tumor suppressor in
breast cancer because they found that it is down-regulated in a lot of breast
cancer cell lines and breast cancer tissues,” said Univ. of Illinois medical
biochemistry professor Lin-Feng Chen, who led the study. But no previous
studies uncovered direct evidence to support that idea, he said.
In the new study, Chen and his colleagues at Nagasaki Univ. discovered that a significant
proportion of mice lacking one of two Runx3 genes spontaneously developed
mammary gland tumors at 14 or 15 months of life—an age corresponding to age 40
to 50 in humans.
“We found mammary tumors growing in about 20% of the female
mice lacking a copy of the Runx3 gene,” Chen said. None of the mice with two
normal copies of the gene developed tumors.
The researchers also found that estrogen receptor alpha
(ER-alpha), a well-known culprit in the development of many breast tumors, was
up-regulated in the mouse tumors. ER-alpha is overexpressed in about 75% of
human cases of breast cancer, and enhanced ER-alpha expression in normal breast
tissue is associated with an increased risk of breast cancer, Chen said.
Circulating estrogen binds to ER-alpha and initiates a chain
of events that alter gene expression in the targeted cell. This is a normal
part of cellular signaling, but in ER-positive breast cancers, the
overexpression of ER-alpha leads to enhanced tumor cell survival, growth, and
proliferation.
The researchers found that when Runx3 was re-introduced into
ER-alpha positive breast cancer cell lines, it suppressed the growth of the
cancer cells and inhibited the potential of the cancer cells to form tumors in
the mouse. Further experiments revealed that Runx3 actually targeted ER-alpha
signaling by inducing the degradation of ER-alpha.
“By regulating the cellular levels of ER-alpha, Runx3
appears to control the cell’s response to circulating estrogen, thus playing an
important role in the onset of breast cancer,” Chen said.
Chen sees three potential benefits that spring from this
study. First, the researchers have discovered a mouse model of spontaneously
occurring mammary tumors that corresponds to an age of increased risk of breast
cancer in humans.
Second, Chen hopes to develop a simple test to measure Runx3
levels in mammary tissue.
“We know from other people’s studies that Runx3 is
inactivated in the early stages of breast cancer,” he said. “So we might be
able to use Runx3 as a biomarker of early stage breast cancer.”
And third, since the Runx3 gene appears to be intact but
inactivated in breast cancer, future studies will focus on reversing its
inactivation, Chen said.
“If you can reactivate Runx3, then you can suppress tumor
growth,” he said.
