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A
new promising enzyme target area for a specific case of breast cancer, Brk,
has been identified in research published on August 21, 2008 in
the Proceedings of the National Academy of Sciences
(PNAS.)
In
a specific subset of breast cancer patients, the neoplasm cells create
high levels of the protein ErbB2 (also called HER2) which pushes the
cells to proliferate without limit, a characteristic common of all
cancers. Approximately one in four patients are in this grouping, and
their clinical prognoses are considerably worse than other patients.
While Herceptin and Lapatinib, concomitantly administered with other
chemotherapic agents, suffer improved the prognosis for many of these
patients, there is significant electric potential for development in this area.
In particular, they ar able to suppress ErbB2, but are not effective
against all tumors that secrete it. Additionally, when patients' tumors
do respond, they commonly become tolerant over time.
According
to the authors of this field of study, led by Professor Senthil Muthuswamy, Ph.D
of the Cold Spring Harbor Laboratories, this suggested that another
component might factor into the progression of these tumors. "The limited
success of existing therapy suggested to us that factors
as well ErbB2, or proteins that collude with ErbB2, might nullify the
effects of Herceptin and Lapatinib," explained Dr.
Muthuswamy.
ErbB2 is a type of molecule known as a receptor tyrosine kinases.
Implicated in many cancers, these molecules occupy on the surface of
the cell and observe cues in the encompassing environment which signal
the cells to proliferate. In breast cancers, this overrun or
ErbB2 in breast cancers are due to a gene chromosomal mutation resulting in
multiple copies of the gene.
Brk
is another protein that undergoes this
sort of gain due to multiple copies of its gene in the genome.
This study focused on the potential link with Brk, which was previously
shown to be over-produced in many types of cancers, including
two-thirds of all breast cancers. By analyzing the genomes of several
breast crab patients helped showed an association between ErbB2 and
Brk. To do this, they forced the production of both agents in the same
cells, and noting the way of life they worked together, to see if they were
over-produced in tandem.
The
team examined tissue from more than two hundred patients for variations
in the genome that could lead to multiple copies of both genes. In
these samples, both proteins were amplified abnormally. Re-analyzing
for the proteins themselves, rather than the genes, also indicated that
the proteins were also over-expressed and thusly in higher concentrations
in the patients' cells. This indicates that both mightiness play an
important character in the development of this type of crab, and so
should both be targetted. "Our results might explicate why the strategy
of using ErbB2 inhibitors
solitary to treat breast cancers has fallen short," said Dr. Muthuswamy.
"These findings may also intimate a way to treat patients with advanced
ErbB2-positive tumors and those who've developed resistance to ErbB2
inhibitors -- an idea that we're eager to test."
In further
experimentation, it became clear to the team that Brk was not capable, in
isolation, to cause cancerous proilferation, and rather enhanced the
proliferation of cells besides expressing ErbB2 by accelerating their
entry into the cell cycle. According to Dr. Muthuswamy, it may be
useful to think of these proteins as factors in driving a car: "If
ErbB2 is the accelerator that makes the car move, Brk helps shift the
gear to gain more than speed."
Thus, Brk helps these tumors become
virulent. Additionally, the team was able to implicate Brk in the
drug-resistant properties of some of these tumors. This indicates, once
over again, that both must be targeted in future therapies. According to
Muthuswamy: "We power need to hit ErbB2-expressing cancers with drugs
against both ErbB2 and Brk."
Brk might likewise be targeted in
isolation. The scientists believe this to be a reasonable strategy
because Brk influence appears to be specific to these cancer cells.
"Brk does non promote the proliferation of normal cells, and its
expression in normal tissues is restricted to non-proliferating cells."
Thus, many side effects that could be caused by other drugs, which
target less specific chemicals, or ar in higher levels in the cells.
Finally, Brk might own use in dianosing chest cancer. "We also think
that Brk would be an ideal clinical mark than could be
used to leave both a diagnosis and prognosis for breast cancer,"
states
Dr. Muthuswamy.
Brk is coamplified with ErbB2 to promote proliferation in
chest cancer
Bin Xiang, Kiranam Chatti, Haoqun Qiu, B. Lakshmi, Alexander Krasnitz,
Jim Hicks, Min Yu, W. Todd Miller, and Senthil K. Muthuswamy.
Proceedings of the National Academy of Sciences,
August 21, 2008
interior Department: 10.1073/pnas.0805009105
Click Here For Journal
About Cold Spring Harbor Labs:
CSHL is a private, not-for-profit research and education institution
dedicated to exploring molecular biology and genetics in order to
advance the understanding and ability to diagnose and treat cancers,
neurological diseases, and early causes of human distress. For more than
information, please visit hTTP://www.cshl.edu
.
Written by Anna Sophia McKenney
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