From Stage 0 to Invasive: Study Uncovers How Obesity Influences Molecular Pathways in Breast Cancer Progression

A novel study has found that obesity is associated with a distinct molecular program driving the transition from early-stage, premalignant breast lesions to invasive breast cancer. Rather than simply showing increased activation of classical invasive pathways, tumors from obese patients exhibited a distinct stress-adaptive phenotype. The findings from the studyopens in new tab/window in The American Journal of Pathologyopens in new tab/window, published by Elsevier, suggest that metabolic health could be an important factor in future risk stratification and treatment decision-making.

Obesity is a major and increasing risk factor for breast cancer. Ductal carcinoma in situ (DCIS), often referred to as stage 0, accounts for nearly 25% 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.

There are still many unknowns regarding the molecular mechanisms and how obesity exactly impacts the progression of early-stage, premalignant breast lesions to invasive breast cancer.

“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,” explains lead investigator Elizabeth A. Wellberg, PhD, Department of Pathology, Stephenson Cancer Center, and the Harold Hamm Diabetes Center, University of Oklahoma Health Campus. “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.”

The researchers found that rather than being dominated by classical proliferative and epithelial-to-mesenchymal transition pathways, tumors arising in an obese setting may follow a fundamentally different invasive program driven by metabolic stress adaptation, inflammation, and remodeling of the tumor microenvironment. This was accompanied by an increased sulfatase 2 (SULF2) expression, suggesting that obesity may influence both tumor biology and prognostic interpretation.

“Our study highlights that progression from DCIS to invasive disease is not driven by tumor cells alone. Instead, invasion appears to involve extensive cooperation between epithelial, stromal, and immune cell populations, and obesity influences all of these compartments as well as the signaling interactions between them,” says co-lead investigator Bethany N. Hannafon, PhD, Departments of Obstetrics and Gynecology, Cell Biology, and Pathology, and Stephenson Cancer Center, University of Oklahoma Health Campus.

Dr. Wellberg adds, “An important aspect of this work is the recognition that molecular indicators of progression need to be interpreted within their local tissue context. By using spatial transcriptomics, we were able to examine how distinct cell populations interact within the tumor microenvironment, revealing patterns that would likely be obscured in traditional bulk tissue analyses.”

These 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.

In addition, the identification of pathways associated with oxidative stress, inflammatory signaling, and extracellular matrix remodeling, including upregulation of SULF2, may help identify new therapeutic targets specifically relevant to the progression of obesity-associated breast cancer.

Co-investigator Cole Hladik, PhD, Department of Cell Biology, University of Oklahoma Health Campus, concludes, “Our findings suggest that assessing cancer cell-specific markers alone may not fully capture the biological context driving disease progression, particularly in patients with metabolic dysfunction. This study highlights the potential importance of incorporating metabolic factors such as obesity and diabetes into breast cancer risk stratification and treatment planning.”

Notes for editors

The article is “Spatially Resolved Obesity-Driven Molecular Changes in Early Breast Cancer,” by Cole Hladik, Malika Sekhri, Haoning Howard Cen, Sugantha Priya Elayapillai, Schuyler Lee, Bifeng Gao, William Dooley, Ty Milligan, Haddon Hill, Alexander Filatenkov, Elizabeth A. Wellberg, and Bethany N. Hannafon (https://doi.org/10.1016/j.ajpath.2026.03.016opens in new tab/window). It appears in The American Journal of Pathology, volume 196, issue 7 (July 2026), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(26)00124-0/fulltextopens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window to request a PDF of the article or more information. To reach the study’s lead authors, contact Bethany N. Hannafon, PhD, at +1 405 271 8001 extension 48895 or [email protected]opens in new tab/window.

This study was primarily supported by funding from the Harold Hamm Diabetes Center and the Stephenson Cancer Center at the University of Oklahoma Health Campus.

About The American Journal of Pathology

The American Journal of Pathologyopens in new tab/window, official journal of the American Society for Investigative Pathologyopens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.orgopens in new tab/window

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