Phalloidin (red) stained cell (cytoskeleton) and DAPI (blue) stained (DNA) of cells after treatment with exosomes from mice on a high-fat diet. They show extended branching and cytoskeleton reorganization, indicating a strong “muscle” so they can move better, thus showing the potential of being more aggressive in terms of migration and invasion of tumoral cells.

Research

Determining Obesity’s Role in Triple-Negative Breast Cancer

Breast cancer is the most commonly diagnosed cancer among women worldwide and represents a major public health concern due to its high incidence and significant mortality rates. In the U.S. alone, approximately 297,790 new cases of invasive breast cancer were reported in women in 2023, resulting in an estimated 43,700 deaths.

Among the various subtypes of breast cancer, triple-negative breast cancer (TNBC) stands out due to its aggressive nature and poor prognosis. It is characterized by the absence of three critical hormone receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, which are common targets for breast cancer therapies. Consequently, TNBC lacks targeted treatment options, relying primarily on conventional cytotoxic therapies, often referred to as chemotherapy in which drugs kill or damage cancer cells. This limitation contributes to the subtype’s high recurrence rates and significantly lower survival rates compared to other forms of breast cancer.

BU researchers have now discovered that exosomes—messenger nanovesicles that carry proteins, RNA, and other molecules to other cells—released into the blood by different organs and tissues in obese, insulin-resistant models, carry signals that turn otherwise slow-moving TNBC cells into highly mobile, invasive cells. This is the first time a study has shown that exosomes from an obese, diabetic environment directly cause this aggressive change in TNBC, and that Rho-proteins (molecular switches that turn “on” or turn “off” signal transduction pathways) play a key role in driving the change.

“Obesity and type 2 diabetes are very common and already known to worsen many cancers. Our research shows one clear biological way, via exosomes, how being obese can make a deadly breast cancer subtype even more aggressive,” explained first author Pablo Llevenes, a PhD candidate in biomolecular pharmacology at Boston University Chobanian & Avedisian School of Medicine.

The researchers used two groups of experimental models that consumed different diets for three months. One group was fed a high-fat diet that made them overweight and insulin-resistant, while the other group ate a low-fat diet and stayed lean. After 12 weeks, exosomes were collected from the blood and fat tissue of both sets of models. The researchers then added those exosomes to cultured TNBC cells for three days to see how the cells changed shape and moved. Next, they injected those treated cancer cells into healthy models and after four weeks, they removed the lungs and brains, isolated the cancer cells, and grew them in dishes to count the number of colonies formed, visualizing this way the metastatic burden  and allowing them to compare how exosomes from obese versus lean models affected the cancer’s ability to spread.

According to the researchers, by revealing how obesity-driven exosomes push aggressive breast cancer to spread, they hope to unlock new blood tests and drug targets, like Rho-protein inhibitors that stop this deadly process. “These findings support the development of clinical tests to quantify obesity-derived exosomes in patient plasma as noninvasive biomarkers of metastatic risk, allowing earlier identification and tailored management of aggressive TNBC. Ultimately, our goal is to improve survival and quality of life for patients facing both metabolic disease and hard-to-treat cancers,” says corresponding author Gerald V. Denis, PhD, MSc, Shipley Prostate Cancer Research Professor and professor of pharmacology, physiology & biophysics.

These findings appear online in the journal BMC Cancer.