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Developmental Biology - Breast Cancer
Do Aggressive Breast Cancers Store Their Own Energy?
New finding suggests a potential target that may slow or even prevent breast cancer metastasis...
Aggressive breast cancer appears to be able to store large amounts of energy, enabling this cancer's ability to spread. Recent findings suggest glycogen deposits may be a potential target in cancer metabolism that could slow or even prevent breast cancer metastasis.
Cancer cells - especially the more aggressive ones - seem to have an ability to adapt and change in order to evade treatment and spread through the body. But how a cancer cell gets its energy has always foiled detection.
"We wondered if a cancer cell that wants to change its function can redirect energy not because it takes on new energy — but because it has a stored reservoir of potential energy."
Sofia D. Merajver MD PhD, Professor, Internal Medicine and Epidemiology, University of Michigan; and University of Michigan Rogel Cancer Center.
Looking into agressive tumors, Merajver's lab found that levels of glycogen — a stored collection of Glucose molecules which converts to energy — is used by cancers to grow, spread and metastasize.
The team measured glycogen levels in cell lines representing triple-negative breast cancer, inflammatory breast cancer, hormone receptor positive breast cancer as well as in normal breast cells. They have just published their study results in PLOS ONE, revealing that aggressive cancers stored glycogen in very large amounts, on the order of what's stored in the liver — an organ whose key function is storing glycogen.
"It was surprising just how much glycogen these cancer cells were storing. This means the cancer cells have that whole amount of glycogen ready to break down into glucose molecules as need arises."
Sofia D. Merajver MD PhD.
Even more surprising, the researchers found an enzyme controlling glycogen degradation in the brain plays a key role in glycogen control in breast cancer. The enzyme Glycogen phosphorylase or PYG exists in the brain and liver, but is primarily expressed in the brain and identified as PYGB. When researchers knocked out PYGB in breast cancer cells, they found the cells could not use these energy stores and became much less aggressive. They did not see the same effect within normal breast cells.
"This is a completely new way to look at the plasticity of breast cancer cells. We think that this ability to change - for breast cancer cells to rewire themselves depending on their environment - is why many patients become resistant to precision medicines. Our study shows one way the cancer cells do this is by creating a reservoir of building blocks or energy."
Sofia D. Merajver MD PhD.
The researchers believe PYGB could be a potential target to treat or prevent breast cancer metastases, and will conduct further studies will explore this link using animal models. They will also investigate whether glycogen phosphorylases inhibitors, which have been studied in diabetes and heart disease, might slow or stop cancer metastasis.
Abstract
In breast cancer, tumor hypoxia has been linked to poor prognosis and increased metastasis. Hypoxia activates transcriptional programs in cancer cells that lead to increased motility and invasion, as well as various metabolic changes. One of these metabolic changes, an increase in glycogen metabolism, has been further associated with protection from reactive oxygen species damage that may lead to premature senescence. Here we report that breast cancer cells significantly increase glycogen stores in response to hypoxia. We found that knockdown of the brain isoform of an enzyme that catalyzes glycogen breakdown, glycogen phosphorylase B (PYGB), but not the liver isoform, PYGL, inhibited glycogen utilization in estrogen receptor negative and positive breast cancer cells; whereas both independently inhibited glycogen utilization in the normal-like breast epithelial cell line MCF-10A. Functionally, PYGB knockdown and the resulting inhibition of glycogen utilization resulted in significantly decreased wound-healing capability in MCF-7 cells and a decrease in invasive potential of MDA-MB-231 cells. Thus, we identify PYGB as a novel metabolic target with potential applications in the management and/or prevention of metastasis in breast cancer.
Authors
Megan A. Altemus, Laura E. Goo, Andrew C. Little, Joel A. Yates, Hannah G. Cheriyan, Zhi Fen Wu and Sofia D. Merajver.
Acknowledgments
The authors thank Dr. Costas Lyssiotis for input during these studies. The authors also acknowledge the University of Michigan Vector Core, University of Michigan Flow Cytometry Core, and University of Michigan Rogel Cancer Center for provision of institutional core resources utilized in the study.
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Oct 7 2019 Fetal Timeline Maternal Timeline News
The glycogen phosphorylase enzyme, or PYG, exists largely in our brain and liver, primarily functioning in the brain for its high energy needs. It is identified as PYGB. This enzyme controls the breakdown of glycogen and may promote cancer metastasis. It is key in controlling the glycogen molecule and an exciting announcement as October is Breast Cancer Awareness month. CREDIT Wikipedia.
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