Abstract PS4-10-22: Obesity and Triple Negative Breast Cancer: Untangling the Connection

Abstract Breast Cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among U.S. women. In recent years, alongside with increased BC incidence, the increasing number of overweight and obese people is also a major health concern in the U.S. Obesity is a risk factor for BC and has been linked to high rates of BC recurrence and deaths, yet how it affects BC tumor growth and progression is not fully understood. Here, we analyzed the clinical information collected from 531 patients who received a BC diagnosis at the University of South Alabama Mitchell Cancer Institute Clinics between January 2024 and April 2025. Patients were categorized into three groups based on their body mass index (BMI): normal weight (BMI < 25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30). BC patients were most commonly diagnosed with Luminal A BC (64%), followed by TNBC (18%), Luminal B BC (14%), and HER2-enriched BC (4%). Obese BC patients constituted the largest proportion of BC patients in all individual molecular BC subtypes. Interestingly, we observed that for patients with TNBC only, the prevalence of obesity was higher among individuals under 50 years of age (52%) compared to those aged 50 and over (44%). In addition, obese TNBC patients presented with grade 2 and 3 tumors that were characterized by higher Ki-67 levels compared to tumors from grade-matched normal-weight TNBC patients. These findings link obesity to increased TNBC incidence, particularly in young women aged under 50, and suggest an association between obesity and TNBC aggressiveness. To further study the impact of obesity on TNBC progression, we used a mouse model of diet-induced obesity where young female BALB/c mice were fed either a control or high-fat diet (60% kcals) for 12 weeks. To establish primary tumors, murine 4T1-luc2 TNBC cells were injected into the fourth mammary fat pads of lean or obese mice, and tumor growth and progression were monitored. Our results indicated that obese mice experienced an earlier onset of BC and accelerated tumor growth compared to their lean counterparts. One week after tumor transplantation, tumor incidence was found to be 83.3% in the obese group as opposed to 50% in the lean group. Moreover, our immunohistochemistry analysis showed that tumors that grew in obese mice exhibited increased cellular proliferation (Ki-67). In addition, angiogenesis and lymphangiogenesis, the two important processes that facilitate the metastatic dissemination of BC cells, were significantly upregulated in the tumors from obese mice compared to those from lean mice. Interestingly, our RNA-seq data also revealed significant differences in the expression of metastatic-related genes between the 4T1 tumors of lean and obese mice. Studies identifying the factors in the obese tumor microenvironment that make these tumors more aggressive and enhance their metastatic potential will open up exciting new avenues for BC treatment. Citation Format: B. Kola, S. Kakkat, P. Suman, S. Atterberry, A. Richter, K. Sawrie, R. Gupta, A. Mahadevan, C. Nelson, D. Chakroborty, C. Sarkar. Obesity and Triple Negative Breast Cancer: Untangling the Connection [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-10-22.