More than 120 million Americans suffer from diabetes or pre-diabetes. Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, and TNBC patients with obesity-driven diabetes often have worse outcomes.

A new study by researchers from Boston University Chobanian & Avedisian School of Medicine helps explain why this happens and suggests a potential way to improve treatment for these patients.

At present, oncologists do not consider patients with breast cancer and obesity-driven diabetes differently in any significant way from patients with breast cancer who are otherwise healthy.

The new study, "Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes," published in Molecular Cancer Research, a journal of the American Association for Cancer Research, shows that diabetes changes the biology of breast cancer, suggesting the need for special consideration for patients who are at much higher risk for brain metastasis and should be monitored and treated differently than most breast cancer patients.

"We hope our study will lead to better treatments for patients with aggressive breast cancer, especially those with metabolic disorders like diabetes. By uncovering how cancer and metabolism are connected, we move one step closer to more personalised and effective therapies," said corresponding author Gerald V. Denis, PhD, MSc, Shipley Prostate Cancer Research Professor and professor of pharmacology, physiology & biophysics.

Researchers collected exosomes from fat cells and studied how the microRNAs they contain worsen TNBC cell behaviour. They then added these exosomes to cancer cells in lab experiments, and experimental models of breast cancer metastasis, and observed dangerous changes in their growth, movement, ability to survive under stress and colonise the brain. They found that microRNAs, which are involved in many biological processes, including cell differentiation and insulin secretion, are carried in the exosomes and promote aggressiveness in triple-negative breast cancer, especially increasing brain metastasis.

Researchers also analysed breast cancer patient data to see how these microRNAs are linked to cancer progression. The novel patterns found in models directly predict breast cancer patient survival and help explain why some patients with obesity-driven insulin resistance and diabetes experience worse breast cancer outcomes, and suggest a new way to target the disease.

"Our study highlights the growing understanding that cancer does not develop in isolation -- it is influenced by a person's overall health, including metabolic conditions like diabetes. This problem is urgent because the epidemic of obesity-driven diabetes is worsening and now affects over 537 million adults worldwide. This finding adds to the idea that treating underlying conditions, not just cancer itself, could improve patient outcomes," said Denis, who also is co-director of the BU-BMC Cancer Center.

Other BU researchers who worked on this study include graduate research assistants Yuhan Qiu, Andrew Chen and Pablo Llevenes, Michael Seen, MS, Naomi Y. Ko, MD, MPH, and Stefano Monti, PhD.

This work was supported by grants from NIH: U01CA182898, U01CA243004 and R01CA222170 to G.V. Denis.