Researchers Identify Specific Metabolic Pathway in Triple-Negative Breast Cancer

While metabolic pathways in breast cancer have been difficult to identify, researchers at the University of California (UC) Berkeley have discovered a new target in triple-negative breast cancer (TNBC).

“We were looking for targets that drive cancer metabolism in triple-negative breast cancer, and we found one that was very specific to this type of cancer,” said Daniel K. Nomura, PhD, an associate professor of chemistry and of nutritional sciences and toxicology at UC Berkeley, in a news release. Dr. Nomura is the senior author for the study first published in the May 12 issue of Cell Chemical Biology.

TNBC is estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and hormone epidermal growth factor (HER2)-negative, and thus doesn't respond to hormone therapies or targeted therapies. It is even more difficult to treat once is has metastasized.

Dr. Nomura and his team discovered that cells from TNBC cells rely on activity the glutathione-S-transferase Pi1 (GSTP1) enzyme. In cancer cells, they observed, GSTP1 regulates glycolysis, and that inhibition of GSTP1 impairs glycolytic metabolism in TNBC cells, preventing them from getting energy, nutrients, and signaling capability. Normal cells do not rely as much on this particular metabolic pathway to obtain usable chemical energy, but cells within many tumors heavily favor glycolysis.

Co-author Eranthie Weerapana, PhD, an associate professor of chemistry at Boston College, developed a molecule named LAS17 that tightly and irreversibly attaches to the target site on the GSTP1 molecule. By binding tightly to GSTP1, LAS17 inhibits activity of the enzyme. The researchers found that LAS17 was highly specific for GSTP1, and did not attach to other proteins in cells.

Test mice did not experience toxic events and LAS17 shrank tumors grown to an invasive stage from surgically transplanted, human, TNBC cells that had long been maintained in lab cultures, according to Dr. Nomura. Later phases of this research will reveal more about its' capability in human patients. The team will next study tumor tissue resected from human TNBC and transplanted into mice.