There is a slight increase in the risk of developing breast cancer among women with type 2 diabetes. A decreased level of estrogen as a result of insulin resistance increases the risk of developing cancer in any organ. Previous studies have revealed associations between the two diseases. However, the underlying mechanisms for this link have not been fully understood. Now, a mouse study by a team of researchers led by scientists at the University of California, San Diego (UCSD) School of Medicine demonstrates that breast cancer-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. Their findings reveal a possible biological mechanism connecting the two diseases, in which breast cancer suppresses the production of insulin, resulting in diabetes, and the impairment of blood sugar control promotes tumor growth.

The findings are published in the journal Nature Cell Biology in a paper titled, “Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumor growth.”

“Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism,” wrote the researchers. “However, how BC influences glucose homeostasis remains unknown. We show that BC-derived EVs suppress pancreatic insulin secretion to impair glucose homeostasis.”

“No disease is an island because no cell lives alone,” said corresponding study author Shizhen Emily Wang, PhD, professor of pathology at UCSD School of Medicine. “In this study, we describe how breast cancer cells impair the function of pancreatic islets to make them produce less insulin than needed, leading to higher blood glucose levels in breast cancer patients compared to females without cancer.”

Wang said the study was inspired by early work and guidance from Jerrold Olefsky, MD, professor of medicine and associate dean for scientific affairs in the division of endocrinology and metabolism at UCSD School of Medicine. Olefsky is co-senior author of the study with Wang.

Wang and Olefsky found EVs to be the culprit.

In this case, the cancer cells were found to be secreting microRNA-122 into the vesicles. The researchers observed that when the vesicles reach the pancreas, they can enter the islet cells responsible for insulin production, dispense their miR-122 cargo, and damage the islets’ critical function in maintaining a normal blood glucose level.

“Cancer cells have a sweet tooth,” Wang said. “They use more glucose than healthy cells in order to fuel tumor growth, and this has been the basis for PET scans in cancer detection. By increasing blood glucose that can be easily used by cancer cells, breast tumors make their own favorite food and, meanwhile, deprive this essential nutrient from normal cells.”

“These findings support a greater need for diabetes screening and prevention among breast cancer patients and survivors,” said Wang, noting that an inhibitor of miR-122, developed by Regulus Therapeutics, is currently in a clinical trial as a potential treatment for chronic hepatitis C. It has been found to be effective in restoring normal insulin production and suppressing tumor growth in mouse models of breast cancer.

“These miR-122 inhibitors, which happen to be the first miRNA-based drugs to enter clinical trials, might have a new use in breast cancer therapy,” Wang concluded.

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