There is a growing interest in studying the metabolic
function of cancer. New research from Thomas Jefferson University shows that breast cancer cells rely on a different process for turning fuel into energy than normal cells. The results were recently published in the Journal of Biological Chemistry.
Ubaldo Martinez-Outschoorn, Assistant
Professor in the Department of Medical Oncology at Thomas Jefferson
University and researcher at the Sidney Kimmel Cancer Center at Jefferson, said, "The better we understand how cancers thrive, the better we'll be able to cut off the energy supply they need for survival."
‘A protein called TIGAR (short for TP53 inducible glycolysis and apoptosis regulator) promotes the growth of breast cancer by altering cell metabolism in a way that could be targeted with existing drugs.’
Dr. Martinez-Outschoorn and colleagues looked at a protein that they
knew changed the metabolism of breast cancer cells. The protein TIGAR
(short for TP53 inducible glycolysis and apoptosis regulator) diminished
the cell's ability to create energy via the most common biochemical
pathway - converting sugar to energy via glycolysis. But it was unclear
how this change in metabolism altered the cancer cell, or how the cell
was getting the energy it needed to survive.
Through a series of cellular and mouse studies, the researchers
demonstrated that breast cancer cells with a higher-than-normal
abundance of the TIGAR protein were more aggressive and were able to
grow faster than breast cancer cells that had normal amounts of TIGAR.
But if the cells weren't using glycolysis to drive this growth, what
were they using?
Dr. Martinez-Outschoorn and colleagues showed that when cells
expressed TIGAR, they swap their metabolic pathway and become dependent
on mitochondria for energy production. Interestingly, the high levels of
TIGAR produced by cancer cells also changed the metabolism of the cells
that surround and support breast cancer, but with the opposite
metabolic effect. Rather than increase their dependence on mitochondrial
energy production, TIGAR made these supporting cells dependent on
glycolysis and increased tumor growth. Previous studies had shown that
glycolytic supporting cells in tumors make breast cancer more
"The fact that 70-80% of breast cancers show high levels of
TIGAR presents an opportunity," says Dr. Martinez-Outschoorn. "There are
already a number of therapies that block mitochondrial metabolism that
we could use to try to 'starve' breast cancer cells."
Two drugs approved for other indications - metformin, an
antidiabetes therapy and doxycycline, an antibiotic - are known to also
block mitochondrial metabolism. When the researchers used these drugs
to block mitochondrial metabolism in high-TIGAR-expressing breast cancer
cells, they saw a reduction in the cancer's aggressive properties.
"Because these drugs are already approved, they have passed safety
testing in humans. If they indeed help reduce tumor growth in patients,
as our preliminary studies suggest, these drugs could be available to
patients as a combination treatment with other drugs much sooner than
new therapies," says Martinez-Outschoorn.
To that end, Dr. Martinez-Outschoorn is collaborating with Jennifer
Johnson, Assistant Professor of Medical Oncology and Adam
Berger, Professor of Surgery at Jefferson on a clinical trial that
will test the effect of metformin and doxycycline on breast cancers in
women prior to surgery. The study will collect and analyze the tumors of
patients to see if these drugs that inhibit mitochondrial metabolism
might have an effect on tumor biology.