A high-fat diet may play a more significant role in accelerating the growth and spread of triple-negative breast cancer than elevated levels of glucose, insulin, or ketones, according to new research published in APL Bioengineering by AIP Publishing.
In a study led by a multidisciplinary team at Princeton University, researchers found that high-fat nutrient conditions markedly increased tumor growth and invasion in engineered models of triple-negative breast cancer — one of the most aggressive and difficult-to-treat forms of the disease.
“We took the approach of building identical engineered tumors and culturing them in conditions that mimic the blood composition of patients under different dietary states,” said senior author Celeste M. Nelson. “We were hoping to identify dietary conditions that would slow tumor growth. Instead, we found one dietary condition — a high-fat diet — that sped up tumor growth.”
To achieve a more physiologically accurate model, the team engineered tumors using a human plasma-like medium designed to replicate the biochemical environment surrounding cells in the body. This approach enabled researchers to isolate specific nutrients and closely examine how they drive metabolic reprogramming in cancer cells.
The study compared tumor behavior under four metabolic conditions commonly associated with different dietary states: high-insulin, high-glucose, high-ketone, and high-fat. While each condition reflects changes that can occur in the human bloodstream depending on diet, the high-fat environment produced the most pronounced effect, significantly accelerating tumor growth and invasive behavior.
Further analysis revealed that tumors grown in high-fat conditions exhibited elevated levels of MMP1, an enzyme that breaks down the extracellular matrix — the structural framework surrounding cells. Increased MMP1 expression has been linked to poorer clinical outcomes, suggesting a potential mechanism behind the observed increase in tumor aggressiveness.
Triple-negative breast cancer, which lacks estrogen, progesterone, and HER2 receptors, has limited targeted treatment options and is often associated with a worse prognosis. The researchers said their findings could have important implications for dietary guidance in patients undergoing treatment.
Previous studies exploring links between diet and cancer progression have often failed to capture the biological complexity of the human body. Interactions among the immune system, metabolic tissues, and the trillions of microorganisms in the microbiome all influence tumor behavior. Moreover, many laboratory experiments rely on culture media saturated with sugars and nutrients at concentrations that do not reflect real physiological conditions.
“Cells are typically cultured in media that is saturated with sugars and other biochemicals at levels that don’t match what you see in the human body,” Nelson said. “Our study shows that tumor cells behave differently when cultured in media that matches the biochemical composition of human plasma.”
By recreating more realistic nutrient conditions, the Princeton team was able to better simulate how dietary states affect tumors within the body’s continuously circulating interstitial fluid — the water-based solution that bathes cells.
The researchers plan to extend their work to examine how different dietary conditions influence responses to chemotherapy and other treatments.
“We plan to take the same system and define whether tumors respond differently to chemotherapy when cultured in media mimicking the different dietary conditions,” Nelson said. “This would allow physicians to potentially make recommendations about what a patient should eat if prescribed a specific therapy.”
The findings highlight the potential importance of diet in shaping tumor biology and may open the door to more personalized nutritional strategies for patients with aggressive forms of breast cancer.
