Obesity May Not Just Drive Breast Cancer – It May Remove a Natural Defence
Key Takeaways:
- Researchers at Huntsman Cancer Institute at the University of Utah have identified a lipid, 9S-HODE, that is produced in far greater quantities by lean fat cells in the breast than by fat cells affected by obesity – and that helps drive cancerous cells towards their own destruction.
- The finding reframes the relationship between obesity and breast cancer: rather than obesity simply adding a harmful influence, it may also remove a protective one that the body would otherwise supply for itself.
- In preclinical mouse models, restoring 9S-HODE levels in fat cells affected by obesity suppressed breast tumour growth, pointing towards a potentially feasible therapeutic route that works with the body’s existing biology.
A shift in how obesity and cancer risk are understood
A research team at Huntsman Cancer Institute at the University of Utah (the U) has found that obesity prevents a biological process that kills cancerous cells, revealing a possible reason why obesity is a risk factor for breast cancer.
The distinction matters. For years, research into obesity and cancer has largely asked what obesity adds to the picture – inflammation, altered hormone signalling, metabolic disruption. This study asks a different question: what does obesity take away?
“We uncovered the role of a molecule that normally appears in lean tissue that restrains breast cancer growth but is less present with obesity. We know obesity is often a driver of breast cancer, and researchers in our field usually consider how obesity is promoting the disease. But we hadn’t really considered that obesity could also be the loss of something that naturally protects us.” – Keren Hilgendorf, PhD, Huntsman Cancer Institute investigator, assistant professor of biochemistry, University of Utah, and senior author of the study
Hilgendorf and first author Meghan Curtin, doctoral candidate in molecular biology at the U, have published the transformative results of their research in the prestigious journal Science.
Why breast tissue is a special case
Breasts are mostly composed of fat, particularly fat cells called adipocytes. These adipocytes are different depending on a person’s weight and can be lean or obese. In obesity, adipocytes are larger than in their lean counterparts. Hilgendorf also says that the two types of adipocytes generate distinctive microenvironments for cancer cells.
That last point is the crux of the work. Adipocytes are not inert padding around the glandular tissue of the breast – they are metabolically active cells that shape the chemical environment in which any developing cancer must survive. Two people can therefore have breast tissue that looks superficially similar but that behaves very differently at a molecular level, depending on the state of the fat cells within it.
Identifying 9S-HODE
In preclinical models, including breast tissues from donors, Hilgendorf and Curtin found that one of those key differences is the production of a lipid, or fatty acid, known as 9S-HODE.
9S-HODE plays an important role in promoting cell death, particularly a kind of cell death called ferroptosis. This is one way the body purges old and damaged cells, including cells that could be cancerous.
Ferroptosis is, in effect, part of the body’s routine quality control. Cells that are damaged or behaving abnormally are cleared before they can cause harm. A tissue environment that supports ferroptosis is therefore a hostile one for early cancerous cells; an environment that does not support it is considerably more permissive.
What the lean and obese microenvironments do differently
“We found that the lean adipocytes produce much more 9S-HODE than obese ones. This means that cancerous cells die more readily in lean tissue,” says Curtin. “By producing more 9S-HODE, our bodies are actively protecting us, under lean circumstances, in a way it cannot with obesity.”
In other words, the protective mechanism is not switched off entirely in people living with obesity – it is diminished. The supply of the lipid that helps push cancerous cells towards ferroptosis falls away, and with it one of the local defences that breast tissue would otherwise mount on its own behalf.
Restoring the lost signal in preclinical models
In their preclinical mouse models, Hilgendorf and Curtin found that increasing the amount of 9S-HODE in obese adipocytes suppressed breast cancer tumour growth. They believe this new understanding could lead to better therapies.
This is the step that moves the work from observation to intervention. Demonstrating that a molecule is absent is one thing; demonstrating that putting it back changes the trajectory of tumour growth is another, and it is what gives the finding its clinical interest.
“From a clinical perspective, this discovery is incredibly empowering. Because 9S-HODE is naturally present in the body but is lost with obesity, we may be able to restore this protection by putting it back,” says Hilgendorf. “That could become a very feasible therapeutic approach to slow breast cancer growth.”
A therapy built on replacing something the body already makes is, in principle, a more tractable proposition than one built on introducing an entirely foreign agent – though that remains a possibility to be tested rather than an established treatment.
Important caveats
Hilgendorf and Curtin recognize that obesity is just one factor that contributes to breast cancer and that the disease can develop for other reasons. They also say that 9S-HODE seems to be primarily produced by fat cells in the breast, though other fat cells throughout the body may have a similar protective function that will require more research.
Two limits are worth holding onto. First, breast cancer is multifactorial, and no single mechanism accounts for an individual’s risk. Second, the 9S-HODE signal appears to be a local one, generated by fat cells within the breast itself – whether adipose tissue elsewhere in the body performs a comparable protective role for other cancers is an open question.
For clinicians who support people living with obesity, findings of this kind reinforce why obesity is increasingly framed as a complex chronic disease with wide-ranging physiological consequences rather than a matter of body weight alone – the understanding that underpins CCH’s CPD short course Obesity Essentials, which examines the biology, drivers and clinical management of obesity across the care pathway.
What comes next
“We believe this shift in the understanding of the roles of lean and obese adipocytes is the start of something. This is just one discovery, and it’s not the end of the road,” says Curtin. “This opened our eyes to new ways to think about science, and hopefully we can harness what our bodies are already doing to make progress against this disease.”
The critical research happening every day at Huntsman Cancer Institute is supported by the National Institutes of Health/National Cancer Institute, including cancer center support grant P30 CA042014, as well as Huntsman Cancer Foundation.
CCH insight
Research like this is changing how obesity is understood at a cellular level – and with it, how healthcare professionals discuss risk, prevention and treatment with the people in their care. CCH’s Obesity Essentials CPD short course gives clinicians a grounded, evidence-based foundation in the science and clinical management of obesity as a chronic disease.
Source: Huntsman Cancer Institute at the University of Utah
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