An enzyme known as AKR1B1 is highly expressed in basal-like breast cancer (BLBC) cells and appears to be an important mediator of cancer aggressiveness and metastatic ability, researchers in China reported. But their work also showed that a diabetes drug — epalrestat, approved in a few countries to treat diabetes-associated peripheral neuropathies by inhibiting AKR1B1 — is a potential therapy for BLBC patients.
BLBC is an aggressive breast cancer subtype found in about 15 percent to 20 percent of patients. Characterized by its ability to spread, or metastasize, very quickly and to induce early recurrence after treatment, it frequently progresses to the lungs and brain. This form of breast cancer still lacks an efficient targeted therapy, and many BLBC patients have a poor prognosis.
BLBC cells activate a specific cellular process called epithelial-mesenchymal transition (EMT), in which cancer cells acquire the characteristics needed for cancer progression and metastasis.
Working with about 800 samples from breast cancer patients, the researchers found that the gene coding for AKR1B1 enzyme was highly expressed in BLBC samples compared to other cancer subtypes.
They found that this increased expression was regulated by another protein, called Twist2, known for its role in activating EMT. The AKR1B1 enzyme was shown to be an important regulator of this process, being necessary for BLBC cells to acquire stem cell-like properties to migrate and invade other organs.
Further experiments with breast cancer animal models confirmed these observations; lowering the levels of AKR1B1 slowed the growth and progression of BLBC tumors.
“Our data clearly suggests that AKR1B1 overexpression represents an oncogenic event that is responsible for the aggressive behaviors of basal-like breast cancer cells,” the study’s senior author, Chenfang Dong, said in a news release.
The authors also tested the efficacy of epalrestat, an aldose reductase inhibitor that blocks AKR1B1 and is approved in Japan (under the brand name, Kinedak) and China (possibly in generic form) to treat diabetes-associated complications. Epalrestat was able to efficiently block the pro-tumor effects of AKR1B1 in breast cancer animal models.
“Since epalrestat is already on the market and has no major adverse side effects, our study provides a proof of principle that it could become a valuable targeted drug for the clinical treatment of basal-like breast cancer,” Dong said.