75 Quick summary: New oncology research from the University of Oklahoma reveals that obesity fundamentally alters the cellular microenvironment of early stage breast cancer, shifting cellular metabolism and activating the enzyme sulfatase 2 to drive progression towards invasive disease. In women with obesity, pre cancerous lesions cooperate with neighbouring epithelial cells and trigger local inflammation to survive under stress, establishing a distinct pathological pathway compared to the rapid cell division seen in patients without obesity. These biological insights carry immense significance for healthcare practice and public policy, offering clinical practitioners the precise molecular targets needed to predict which patients are genuinely at risk of invasive progression and preventing the widespread overtreatment of noninvasive tumours to preserve long term physical and mental well being. Obesity may influence how early-stage Breast Cancer becomes invasive, according to a study by researchers at the University of Oklahoma published in The American Journal of Pathology. Although obesity is a known risk factor for invasive breast cancer, researchers have not fully understood the mechanisms by which early, noninvasive breast lesions progress to invasive disease. The findings could help improve physicians’ ability to predict and treat the disease. In women without Obesity, Breast Cancers showed typical signs associated with invasive progression, including rapid cell division and greater ability to invade nearby tissue. In women with obesity, however, a different set of biological changes appeared to drive that progression. The cancer environment became more inflamed, with immune cells recruited to support tumour growth. Tumour cells also appeared better able to survive under stress, while cellular metabolism shifted, changing how cells use nutrients for energy. “This could be why women with obesity are at higher risk for invasive breast cancer,” said Bethany Hannafon, PhD, co-lead author and assistant professor in the Department of Obstetrics and Gynecology at the Oklahoma. “The changes these cancer cells undergo allow them to survive and thrive.” Researchers also found differences in the cellular environment surrounding the cancer. Epithelial Cells, where tumours originally develop, recruit neighbouring cells to create conditions more favourable to cancer growth. “In women with Obesity, there is cooperation between all the cell types, not just the cancer cells, which helps an early pre-cancerous lesion become an invasive Breast Cancer,” said co-lead author Elizabeth Wellberg, PhD, assistant professor in the Department of Pathology at the Oklahoma. “That may be an area of future study: can a drug or intervention that targets only one cell type disrupt the broader progression process toward invasive cancer?” The team also discovered higher levels of an enzyme called Sulfatase 2 (SULF2) in tumour cells of women with obesity, suggesting it may play an important role in cancer progression and making it a potential target for future research. Understanding what causes Ductal Carcinoma In Situ (DCIS), an early-stage noninvasive tumour, to progress to invasive disease is critical because not all women diagnosed with it will develop invasive cancer, yet many receive the same aggressive treatment. “In women diagnosed with DCIS, about half later develop Invasive Ductal Carcinoma (IDC) that invades surrounding breast tissue. But we currently have no way of determining which women are most at risk. As a result, many women with DCIS receive the same aggressive treatments used for IDC, including surgery, radiation, and sometimes hormone therapy. Overtreatment is a major concern, but if we had better ways of determining risk, unnecessary treatments could be reduced,” said Hannafon. While Breast Cancer survival rates have improved over the past two decades, the incidence of invasive breast cancer has not declined, underscoring the need for better predictive tools. “Obesity is on the rise — 50% of Americans are expected to be obese by 2030,” said 1st author Cole Hladik, PhD, who worked in Hannafon’s lab while earning his doctorate. “That projection further highlights the importance of considering a patient’s metabolic health alongside the biology of the tumour itself.” The study, titled “Spatially Resolved Obesity-Driven Molecular Changes in Early Breast Cancer,” analysed samples from patients treated at the OU Health Stephenson Cancer Center. By identifying specific molecular changes, including elevated levels of Sulfatase 2 (SULF2) and microenvironmental shifts linked to Obesity, researchers hope the findings may eventually help clinicians better assess risk for women with Ductal Carcinoma In Situ (DCIS), reducing unnecessary interventions while improving outcomes for those at higher risk of progression.