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'Second hit' pushes
noninvasive breast cancer towards deadly
metastasis
A new study identifies a molecule that acts cooperatively with a
well known oncoprotein to drive progression
of noninvasive breast cancer to metastatic,
life-threatening disease.
The research findings, published by Cell Press in the September
issue of the journal Cancer Cell,
could have a significant impact on
therapeutic decisions by facilitating
identification of high risk patients.
Elevated ErbB2, a well known invasion and metastasis promoting
protein, is found in about one quarter of
invasive breast cancers (IBC) and is
associated with poor patient survival.
However, ErbB2 is also overexpressed in more than half of
noninvasive ductal carcinomas in situ (DCIS).
DCIS, which is characterized by
proliferation of malignant cells within
mammary ducts with no invasion into
surrounding tissues, is a precursor of IBC.
It is not clear why ErbB2 is more frequently overexpressed in
noninvasive DCIS than in IBC or what drives
the progression of DCIS to IBC.
"For effective reduction of cancer mortality, it is extremely
important to predict the risk of, and to
intervene in, the critical transition from
noninvasive DCIS to life-threatening IBC,"
offers senior study author Dr. Dihua Yu from
the Department of Molecular and Cellular
Oncology at the University of Texas, M. D.
Anderson Center in Houston, Texas.
Previous research has led to the suggestion that additional risk
factors may be needed for the
ErbB2-overexpressing DCIS to transition into
IBC.
Dr. Yu and colleagues examined whether overexpression of 14-3-3?? a
protein that belongs to a family of
evolutionally conserved proteins involved in
cancer progression, could serve as a risk
factor or "second hit" and cooperate with
ErbB2 to drive progression of DCIS to IBC.
The researchers observed that overexpression of both 14-3-3? and
ErbB2 in DCIS was associated with a higher
risk of progressing to IBC.
Elevated ErbB2 increased cell migration while elevated 14-3-3?
decreased cell adhesion, making it more
likely that the malignant cells could escape
from the tissue structure.
"Importantly, patients whose breast tumors overexpressed both ErbB2
and 14-3-3? had higher rates of metastatic
recurrence and death than those whose tumors
overexpressed only one," says Dr. Yu.
The researchers went on to identify pathways downstream of 14-3-3?,
such as the TGF-?/Smads pathway, that may be
amenable to therapeutic intervention.
"Our findings shed more light on the mechanism of the deadly
transition from non-invasive DCIS to the
life-threatening invasive breast cancer, in
addition to solving a long time puzzle
regarding breast cancers that overexpress
ErbB2.
"This study also identified biomarkers that allow selection of
high-risk DCIS patients for more aggressive
treatments at early stages of cancer
development, while saving low-risk patients
from ablative clinical procedures," offers
Dr. Yu.
"Moreover, it provided promising targets for future
intervention strategies to prevent DCIS
progression to IBC."
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