Obesity after menopause increases our risk of breast cancer, but what are the mechanisms behind this?
US researcher Dr Kirsty Brown gave a great overview of how obesity and breast cancer interact at the cellular level at the December 2025 San Antonio Breast Cancer Symposium.
In post-menopausal women, the risk of breast cancer increases by 10% for every 5 BMI units above 25. The evidence for a link with obesity is greatest for oestrogen receptor positive (ER+) breast cancer.
Obesity changes the breast microenvironment
Breasts have a lot of fatty tissue and obesity-related changes to that tissue can change the breast microenvironment, making it more favorable for tumour growth.
Several metabolic pathways such as PI3K, AKT and p53, which are known to be key drivers of cancer growth, are regulated by obesity-related factors in the tumour and the breast microenvironment.
With obesity, adipose (fatty) tissue mass increases and this requires the formation of new blood vessels to supply oxygen and nutrients to the expanding adipocytes (fat cells). Adipocytes have a finite capacity to store lipid (fat) and when lipid droplet sizes are too big the cells become hypoxic (starved of oxygen) and can die. The dying cells release cytokines which induce an immune response and inflammation.
With obesity, fat cells also produce more adipokines such as leptin, a hormone that normally induces feelings of satiety. Obese individuals develop leptin resistance; although they have high levels of this hormone, their central nervous system does not recognise this and they continue to feel hungry even when they are full.
Dr Brown’s team have also recently discovered that adipose tissue can produce extracellular vesicles (tiny membrane-bound sacs that can move between cells) which can stimulate breast cancer proliferation.
Obesity changes hormone levels
The majority of breast cancers are ER+ and occur after menopause. This seems counter-intuitive, as circulating oestrogen levels plummet during menopause as ovarian function changes. However, it is now possible to measure oestrogen produced by adipose tissue in post-menopausal women, showing that women with obesity have significantly higher circulating oestrogen levels than their peers without obesity. Oestrogen in breast tissue drives the growth of ER+ cancer cells.
In addition to these increases in cancer-promoting factors with obesity, there is also a loss of cancer-mitigating factors, such as the adipocyte-derived hormone adiponectin and the gut-derived hormones ghrelin and non-acylated ghrelin. Adiponectin and ghrelin work differently in non-obese and obese adipose tissue.
Metabolic crosstalk between special fat cells in the breast (adipose stromal cells) and breast cancer cells is thought to be critical for the support of tumour growth. Both obesity and breast cancer prompt changes in the way that adipose stromal cells produce aromatase, an enzyme that helps convert androgens to oestrogens. Hunger hormones such as ghrelin can suppress the production of aromatase in the breast.
Exploring new treatment options
As our knowledge of the interconnections between obesity and breast cancer increases, we can identify some potential targets for therapies to reduce risk or treat breast cancer.
Metformin is a drug used to help control blood glucose levels in those with diabetes. Interest in using it for cancer treatment came from the observation that diabetic patients who took it had a reduced propensity to develop cancer. Metformin is a mitochondrial electron transport inhibitor which affects energy metabolism in cells. Interim results from a clinical trial looking at using metformin in addition to current best practice show a reduction in body weight, improvements in metabolic measures and decreased oestradiol levels in post-menopausal women with triple negative breast cancer. It is thought that the results are not just a consequence of body weight reduction, but arise from the drug suppressing drivers of breast cancer growth, including insulin, glucose, oestrogens and adipokines.
Weight loss, achieved by restricting calorie intake and/or increasing exercise, is associated with reduced breast cancer risk and has profound effects on obesity-related risk factors such as levels of sex hormones, inflammation and insulin. The Breast Cancer Weight Loss study is a phase III randomised controlled trial comparing a telephone-based weight loss intervention with and educational control intervention to treat women with overweight or obesity who have early breast cancer. The effects of these treatments on levels of insulin, adipokines and inflammatory markers will also be measured in this study.
When asked about the potential role of modern weight loss drugs such as Wegovy and Ozempic, Dr Brown thought that they might be helpful but said she was not yet certain about that. (You can read more about weight loss drugs and cancer here.)
BMI and BRCA
Women with BRCA1 or BRCA2 germline mutations have an elevated breast cancer risk and many studies have tried to see if their risk could be reduced by weight control. However, results so far have been equivocal.
Dr Brown’s team has studied breast tissue and cells taken from women with BRCA mutations who had with high or low body mass index (BMI). Cells from those with high BMI had greater DNA damage and other biomarkers of metabolic dysfunction. RNA sequencing also showed obesity-associated alterations to the breast adipose microenvironment, including activation of oestrogen biosynthesis which affected neighbouring breast epithelial cells. When tissue explants from these women were treated to block oestrogen synthesis or oestrogen receptor activity, DNA damage was reduced. Other obesity-associated factors, including leptin and insulin, increased DNA damage in the breast cells from these BRCA mutation carriers, and inhibiting those factors decreased DNA damage. This suggests a mechanism linking obesity with elevated breast cancer risk in this population. Maintaining a lower body weight or pharmacologically targeting oestrogen or metabolic dysfunction in people with BRCA mutations may help to reduce their breast cancer risk.
Take home message
This research shows the causative mechanisms underpinning the observed correlation between obesity after menopause and breast cancer.
Obesity has far-reaching and profound impacts on many of our metabolic pathways. Cellular level discoveries reveal the depth and complexity of biological interactions between obesity and breast cancer. Understanding the mechanisms by which obesity promotes breast tumour growth gives us the opportunity to identify new therapeutic targets.
The findings clearly show the value of maintaining a healthy body weight, especially after menopause, to reduce breast cancer risk. They also offer the promise of new evidence-based treatments and interventions in the future.
19 December 2025
