Study Identifies Mechanism Regulating Breast Cancer Aggressiveness

Study Identifies Mechanism Regulating Breast Cancer Aggressiveness

A new study has offered insights into the exact mechanism breast cancer cells undergo in order to become aggressive.

The findings, included in the study “Manganese Superoxide Dismutase Expression Regulates the Switch Between an Epithelial and a Mesenchymal-Like Phenotype in Breast Carcinoma,” and published in the journal Antioxidants & Redox Signaling, show that the switch to these cells becoming more invasive can be traced all the way back to increased intracellular levels of an enzyme called manganese superoxide dismutase (MnSOD), which is an important regulator of the cells’ metabolic redox processes.

The study was conducted by Alan Prem Kumar, MD, professor Shazib Pervaiz, MD, PhD, and associate professor Marie-Veronique Clement, PhD, as part of a collaboration between the Cancer Science Institute of Singapore at the National University of Singapore (NUS) and NUS Yong Loo Lin School of Medicine.

The researchers had previously found that MnSOD levels were particularly higher in triple negative breast cancer cells, a particularly invasive breast cancer subtype with enhanced metastatic capabilities, compared to non-invasive or non-tumorigenic cells. Based on those findings, the team sought to determine the relationship between the intracellular metabolic environment and the tumor’s ability to turn aggressive.

“Our group’s work over the years has highlighted the critical role of cancer cells’ oxidative metabolism in drug resistance and cell survival. This study underscores the importance that MnSOD plays in the biology of breast cancer,” Clement said in a press release.

“MnSOD expression is decreased during the initial stages of cancer development. However, as the cancer advances, MnSOD expression increases and such high MnSOD levels are typically observed in triple negative breast cancer patients,” said Loo Ser Yue, MD, the study’s lead author who also is a former graduate student from NUS Yong Loo Lin School of Medicine. “In fact, we have shown that less aggressive tumors, when artificially made to increase MnSOD antioxidant protein levels, adopt an aggressive behavior.

“Our study shows that the amount of MnSOD levels in the tumor cell determines the predominant reactive oxygen species that will tell the tumor cells whether to stay put, or to transform into an invasive form that is capable of moving to distal parts of the body,” she added.

There is no single treatment for breast cancers and the currently available therapeutic approaches —including chemotherapy, immunotherapy and surgery — do little to improve one’s chances if they have a highly invasive, metastatic cancer subtype such as triple negative breast cancer. By manipulating the MnSOD switch, it is possible that patients with aggressive cancer may become more receptive to conventional treatments.

“By suppressing MnSOD expression or its activity in triple negative breast cancer patients, we are able to make the tumor cells less aggressive and more sensitive to chemotherapy,” said Kumar.

The authors believe these results are important as they may one day lead to new therapies preventing cancer growth and spread by supplementing current treatments with substances that counter MnSOD, making it unavailable to the cell’s microenvironment or downregulating its expression, thus minimizing the tumor’s ability to spread.

“Our study provides a novel mechanism for exploiting cancer’s Achilles heel with potential implications for the design of target-specific therapies against aggressive breast cancer” said Pervaiz.

Of note, the researchers found that the same underlying mechanism may help develop novel therapeutic approaches beyond breast cancers.