Metabolic Syndrome and Obesity in Breast Cancer: Signaling Pathways and Therapeutic Implications
Kristy A. Brown, PhD, University of Kansas Medical Center
Conference:
2025 University of Kansas Breast Cancer Year in Review
Introduction: More Than BMI—Understanding Obesity's Role in Breast Cancer
At the 2025 University of Kansas Breast Cancer Year in Review presented by Total Health, Dr Kristy Brown, a cell biologist and metabolism expert, brought a translational science approach to her presentation on the role of obesity and metabolic syndrome in breast cancer biology. Her central message was that obesity and metabolic health can significantly impact breast cancer development, progression of disease, and response to treatment—not only in patients with hormone receptor–positive (HR+) disease, but also across multiple subtypes of breast cancer. In addition, she noted that the location and function of adipose tissue matter more than its overall quantity.
Beyond BMI: Rethinking Body Composition in Risk Assessment
Dr Brown began by challenging the conventional reliance on body mass index (BMI) as a means to define obesity. She presented data from a 2024 study using the CUN-BAE index (Clínica Universidad de Navarra–Body Adiposity Estimator), which considers both sex and age to more accurately estimate body fat percentage. Using this metric, she noted, the risk for obesity-attributable breast cancer jumped substantively, from 23% (using BMI) to 38%. In this regard, she highlighted the concept of "normal weight obesity"—including those individuals with a BMI <25 but having excess adiposity (>33.3%). “These women are often overlooked in risk stratification,” she warned. “But they're not metabolically healthy.” Dr Brown also noted the findings from one a meta-analysis, wherein each 5% increase in body fat among postmenopausal women was associated with a 15% elevated risk of breast cancer—even in women with “normal” BMI.
The Tumor Microenvironment: A Metabolic and Inflammatory Nexus
Dr Brown reviewed some of the biological underpinnings for these epidemiologic associations, noting that in obesity, mammary adipose tissue becomes inflamed and dysfunctional. This can be characterized by enlarged adipocytes, and increased leptin production, which can promote proliferation and invasion. In addition, obesity may also be characterized by recruitment of M2 macrophages in mammary tissue, forming inflammatory "crown-like" structures, local estrogen synthesis resulting from elevated aromatase expression, and free fatty acid release which can fuel tumor metabolic processes. “Breast cancer doesn’t develop in a vacuum,” she explained. “It emerges in a complex microenvironment, and in obesity, that environment is more permissive to growth and invasion.”
Obesity and Inflammatory Breast Cancer (IBC): A New Link
Dr Brown also noted a recent study out of Cornell Medical Center, presented at the 2024 San Antonio Breast Cancer Symposium (SABCS), which extended the obesity concept to inflammatory breast cancer (IBC)—a rare, aggressive subtype more prevalent in North Africa. Using preclinical models and clinical specimens, investigators in this study found that M2 macrophage infiltration in patients with obesity with IBC was linked to worse five-year survival. A key mediator in this process, Dr Brown noted, is Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), which promotes macrophage infiltration and inflammation, and inhibition of MARCKS reduced invasion and migration in IBC models. “This is a potential target worth exploring,” Dr. Brown said. “It opens the door to metabolic and immune modulation in IBC, a disease with few effective therapies.”
Molecular Crosstalk: Metabolism and Signaling in Cancer Cells
With regard to intracellular mechanisms, Dr Brown detailed how common cellular oncogenes—including PIK3CA, TP53, and STK11— are known to regulate metabolic pathways within cancer cells. In patients with PIK3CA mutations, for example, hyperinsulinemia and hyperglycemia (commonly seen in patients with obesity and type 2 diabetes) may amplify oncogenic signaling, and in turn further accelerate tumor growth. In patients with ER+ tumors, estradiol has been shown to directly induce DNA damage, particularly in BRCA1/2 mutation carriers. In experimental studies, this damage could be blocked with the selective estrogen receptor degrader (SERD) fulvestrant. Commenting on the molecular crosstalk between signaling pathways, Dr Brown noted “These data reinforce the value of estrogen suppression… and also hint at new metabolic vulnerabilities we can exploit.”
Targeting Aromatase and Estrogen Production in the Breast
Dr Brown noted that aromatase, the enzyme that synthesizes estrogen, is known to be overexpressed in breast adipose tissue of women with obesity. Accordingly, this local estrogen production contributes to increased breast cancer risk, particularly after menopause. Experimental studies in Dr Brown's lab showed that activation of AMP-activated protein kinase (AMPK) can suppress aromatase expression and resulting estrogen synthesis. She noted that metformin, an AMPK activator, could dose-dependently reduce estrogen production and resulting DNA damage in breast tissue from BRCA1/2 mutation carriers. “This offers a tantalizing opportunity for targeted prevention,” she said, “especially in high-risk women where estrogen signaling and metabolic stress intersect.”
Obesity and Early-Onset Breast Cancer in Black Women
Obesity can also be a contributor to disparate breast cancer outcomes in underserved populations, including Black women. Citing data from Alabama, Dr Brown highlighted findings that Black women with obesity were disproportionately affected by early-onset breast cancer, despite being overall underrepresented in the population studied. Notably, these women had increased risk of both the luminal A and triple-negative breast cancer (TNBC) subtypes. “Obesity is not just a risk factor—it’s a driver of disparities,” Dr Brown emphasized. Commenting on the paucity of data and frequent underrepresentation of Black women in clinical studies of this type, Dr Brown noted “We need more diverse cohorts and tailored interventions that consider racial and ethnic backgrounds.”
Impact of Obesity on Treatment Tolerance and Chemotherapy Toxicity
Dr Brown also reviewed several studies exploring the role of obesity and sarcopenia (low muscle mass) in chemotherapy outcomes. In one sub analysis of 323 early breast cancer patients, obesity was associated with an increased risk of chemotherapy-related toxicity (odds ratio [OR] = 3.58), especially when coupled with sarcopenia. Dr Brown also noted that patients with obesity were more likely to require chemotherapy, even among patients with early-stage disease, which could relate in part to having higher-risk features and poorer prognostic scores. Another pooled analysis from the MONALEESA trials, however, showed that the cyclin dependent kinase 4/6 inhibitor ribociclib combined with endocrine therapy improved outcomes regardless of patient’s BMI, and those patients with obesity experienced fewer dose reductions and interruptions. Taken together, Dr Brown suggested that toxicity profiles and responses may differ by body composition and therapy type—and that careful dose management is therefore essential.
Metabolic Interventions: Lifestyle and Medication-Based Approaches
Given the modifiable nature of obesity as a risk factor for breast cancer, Dr Brown reviewed data from two prominent lifestyle intervention studies. In the BWEL Trial (N=3,180): A 2-year telephone-based coaching program led to significant improvements in leptin, C-reactive protein (CRP), and insulin levels—key markers which have been linked to both breast cancer recurrence and survival. In the CANcer TOxicities Cohort (France), a prospective study of 10,359 patients, found that ≥5 MET-hours/week of exercise was associated with a significant reduction in distant recurrence-free interval events, especially in HR– and premenopausal populations. Dr Brown also cited a small, randomized trial showing exercise therapy improved chemotherapy dose delivery (RDI) in patients receiving anthracyclines, though tumor response rates were similar to controls.
Emerging Role of GLP-1 Receptor Agonists
With the rise of new anti-obesity medications, Dr Brown addressed the growing interest in GLP-1 receptor agonists (e.g., semaglutide, tirzepatide) in the oncology community. She noted that, in preclinical models, tirzepatide reduced tumor-promoting effects of diet-induced obesity, although tumor mass reduction was less pronounced than with caloric restriction. She further noted that at least three clinical trials are now underway or planned to explore the impact of GLP-1 agonists in breast cancer survivors or patients with residual disease. One cautionary study in this regard suggested possible interference with chemo-immunotherapy in TNBC, though the data remain to be confirmed. Commenting on the impact of the GLP-1 agonists impact, Dr Brown noted “These agents are potent, but we need to proceed with scientific rigor… Weight loss alone doesn’t tell the whole story—we need to understand the biology.”
Closing Message: Precision Prevention in the Age of Obesity
Dr Brown concluded her presentation with a call to action: “Obesity is modifiable, and we’re now starting to understand the biological mechanisms that link it to breast cancer.”
Her suggestions for clinicians were fourfold: 1) Use body composition and metabolic health—not BMI alone—to assess risk, 2) Consider obesity as a therapeutic modulator, not just a comorbid condition, 3) Engage in personalized prevention, especially for high-risk groups like BRCA mutation carriers or young Black women with breast cancer, and 4) Leverage both lifestyle and pharmacologic interventions, guided by biology and emerging biomarkers.
Metabolic Syndrome and Obesity in Breast Cancer: Key Takeaways
Obesity and metabolic syndrome independently drive breast cancer risk, recurrence, and mortality—beyond BMI alone.
The tumor microenvironment in obese individuals is more inflammatory, estrogen-rich, and metabolically active, fostering tumor progression.
Local estrogen production, DNA damage, and macrophage infiltration are key mechanistic links between adiposity and cancer.
Metformin and AMPK activation may suppress estrogen production and DNA damage in high-risk breast tissue.
Lifestyle interventions (e.g., BWEL, exercise) improve biomarkers tied to recurrence and survival.
GLP-1 receptor agonists are promising but must be evaluated rigorously in breast cancer contexts.
You can see the full presentation by Dr Brown from the 2025 University of Kansas Breast Cancer Year in Review here.
Speaker Disclosure Information: Dr Brown reported no relevant disclosures for this presentation.