New survival pathway unearthed in triple-negative breast cancer

Cleveland Clinic building
The survival pathway involves the protein Cx26, which was once thought to suppress cancer progression, but may actually turn out to drive cancer growth. (Marc Buehler/CC BY-NC 2.0)

Aside from chemotherapy, there are few options for patients with triple-negative breast cancer, but new research out of the Cleveland Clinic might change that. The team discovered a potential new target: a stem cell pathway that helps this form of breast cancer survive.

Triple-negative breast cancers are aggressive and difficult to treat because they lack estrogen and progesterone receptors, as well as HER2 overexpression, making targeted hormone therapies ineffective.

The study identified a survival pathway in cancer stem cells, which the Cleveland Clinic researchers believe gets to the crux of why triple-negative breast cancer is so hard to treat. At the center of the pathway is the protein connexin 26 (Cx26), which was previously thought to curb tumor growth but may actually drive tumor progression by aiding communication between cells.

The researchers found that Cx26 is the most highly expressed protein of its kind in triple-negative breast cancer tissue compared to healthy tissue. They also saw that Cx26 levels are higher in cancer stem cells than in noncancer stem cells and that the protein is expressed inside cells instead of on the cell surface. The findings appear in Nature Communications.

"Additional research is needed, but this discovery suggests that inhibiting Cx26 and the related pathway may be a promising new strategy for stopping or preventing triple-negative breast cancer stem cells from self-renewing and spreading," said Justin Lathia, of the Cleveland Clinic Lerner Research Institute, in a statement. "It may also offer a target for diagnostic testing that helps clinicians predict health outcomes and relapse-free survival for patients with a specific cancer type."

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Efforts to fight triple-negative breast cancer with PARP inhibitors have seen mixed results. AstraZeneca’s Lynparza, already approved for ovarian cancer and BRCA-mutated breast cancer, has shown promise in triple-negative breast cancer, boosting progression-free survival by 42%. But AbbVie wasn’t so lucky. In April, two phase 3 trials combining its veliparib and chemotherapy to treat non-small cell lung cancer and triple-negative breast cancer came up short.

"Triple-negative breast cancer is resistant to treatment and has a high recurrence rate," said Ofer Reizes, who led the study alongside Lathia. "This aggressive subtype accounts for about 15% to 20% of breast cancers. Our findings are at an early stage but we are hopeful that targeting these cancer stem cells will lead to new treatments to allow women to be treated successfully and improve their outcomes."