"[W]e now need to push forward the development of CtBP inhibitors as breast cancer drugs. We hope these could lead to new treatment options for breast cancer patients who most need it."Jeremy Blaydes
Sunday, June 30, 2019
Is a diabetes drug the key to aggressive breast cancer?
New research suggests that the drug metformin may be the key to tackling triple-negative breast cancer.
Triple-negative breast cancer is an aggressive form of breast cancer that often results in a poor outlook for people who receive a diagnosis for it.
Most forms of breast cancer depend on hormones, such as estrogen and progesterone, for growth and spread. Therefore, targeting these hormone receptors offers an often successful avenue for treatment.
However, unlike these more widespread forms of breast cancer, triple-negative cancers lack all three hormone receptors: the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2.
As a result, doctors find this form of cancer particularly difficult to target and treat. Triple-negative breast cancers make up approximately 12% of all cancers, and in the United States, this form of cancer is twice as likely to occur in black women than white women.
Recent studies have pointed to cancer stem cells as a potential target in the treatment of triple-negative breast cancer. Cancer stem cells seem to be key for the formation and advancement of triple-negative tumors.
Now, researchers may have found a way to weaken these cells and make tumors more vulnerable to treatment.
Specifically, a team led by Jeremy Blaydes, a reader in Cancer Cell Biology at the University of Southampton in the United Kingdom, found that the diabetes drug metformin changes the metabolism of cancer stem cells, making them easier to target by a new form of treatment.
Blaydes and colleagues detail their findings in the journal Carcinogenesis.
Usually, breast cancer stem cells depend on both oxygen and sugar (glucose) to produce the energy they need to survive and thrive.
However, under dire environmental conditions, these cells can adapt their metabolism to rely more on glucose than oxygen.
Cancer stem cells — like all cells — can break down glucose into smaller energy chunks through the process of glycolysis.
In the new study, Blaydes and team treated breast cancer stem cells with a low dose of metformin, a drug that lowers blood sugar levels in people with type 2 diabetes.
The team applied a low dose of metformin to cultured breast cancer stem cells for an extended period of more than 8 weeks.
Doing so forced the breast cancer cells to develop a glucose "addiction." The cells that became excessively reliant on glucose also displayed higher glycolysis rates, as well as higher activity in a type of protein called "C-terminal binding protein" (CtBP). CtBPs also fuel tumor growth.
Changing the cancer cells' metabolism this way made them more vulnerable to treatment with CtBP-inhibiting drugs.
Overall, applying metformin to the cancer cells, and then "switching off" CtBP genes by using CtBP inhibitors slashed the growth of cancer stem cells by 76%.
"Our work has given us the first glimpse into how changes in metabolism can alter the behavior of breast cancer stem cells and reveal new targets for therapy," comments Blaydes, adding, "We are only beginning to scratch the surface in this area of research."
Next, the researchers plan to refine CtBP inhibitors further and test various combinations of metformin and CtBP inhibitors to stop the spread of triple negative breast cancers.
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