New Delhi: Obesity could be associated with a distinct molecular process driving the transition from an early-stage, premalignant breast lesions to invasive breast cancer, according to a new study.
Researchers, including those from the University of Oklahoma Health Campus, US, said that rather than simply showing an increased activation of classical invasive pathways, tumours from obese patients exhibited a distinct stress-adaptive phenotype.
Tumours arising in an obese context may follow a fundamentally different invasive program driven by a metabolic stress adaptation, inflammation, and a remodelling of the tumour microenvironment, they said.
Metabolic stress adaptation refers to the body’s physiological adjustments to overcome disruptions to cell energy, nutrient or oxygen levels.
The team said that ductal carcinoma in situ (DCIS), often referred to as stage 0, accounts for nearly 25 per cent of all newly detected breast lesions and carries an increased lifetime risk of developing invasive ductal carcinoma (IDC). However, not all DCIS lesions progress to IDC.
“Our study highlights that progression from DCIS to invasive disease is not driven by tumour cells alone. Instead, invasion appears to involve (an) extensive cooperation between epithelial, stromal, and immune cell populations, and obesity influences all of these compartments as well as the signalling interactions between them,” co-lead investigator Bethany N. Hannafon, from the departments of obstetrics and gynaecology, cell biology, and pathology, University of Oklahoma Health Campus, said.
Obesity is a major and increasing risk factor for breast cancer.
Molecular mechanisms which influence how obesity exactly impacts the progression of early-stage, premalignant breast lesions to invasive breast cancer are still unknown, the researchers said.
“A significant clinical challenge in DCIS is determining which lesions are most likely to progress to invasive breast cancer so that patients are not overtreated or undertreated,” lead investigator Elizabeth A. Wellberg, department of pathology at the University of Oklahoma Health Campus, said.
“Using spatial transcriptomic profiling of epithelial, stromal, and immune compartments from DCIS and IDC lesions in obese and non-obese patients, our study investigated how obesity alters the molecular features associated with breast cancer invasion,” Wellberg said. Spatial transcriptomic profiling is a technique that maps gene expression.
The authors wrote, “In non-obese patients, IDC lesions exhibited canonical profiles driven by proliferation and epithelial-to-mesenchymal transition, compared with DCIS.”
They said, “Conversely, the obese setting was characterised by a distinct stress-adaptive phenotype, enriched for metabolic adjustment, oxidative stress response, and inflammatory signalling.”
The result was accompanied by an increased expression of the enzyme ‘sulfatase 2’ (SULF2), suggesting that obesity may influence both tumour biology and prognostic interpretation, the team said. SULF2 is heavily involved in cancer progression and is often a therapeutic target.
The findings suggest that standard prognostic approaches may not fully capture invasive risk in obese patients.
Incorporating metabolic health, immune composition, and obesity-associated molecular features into diagnostic and prognostic models could improve risk stratification and patient management, the researchers said.
