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
Read More
New Research Shows Obesity May Reshape How Breast Cancer Spreads
Key Takeaways:
- Obesity may alter how early, non-invasive breast lesions progress into invasive cancer, a University of Oklahoma study suggests.
- In women with obesity, progression was linked to inflammation, immune cell activity, metabolic changes and raised levels of the enzyme SULF2 – not the rapid cell division seen in women without obesity.
- The findings could improve risk prediction for women with DCIS and help reduce overtreatment.
A different route to invasive disease
Obesity may change how early-stage breast cancer becomes invasive, according to a study by University of Oklahoma researchers published in The American Journal of Pathology.
Obesity is already recognised as a risk factor for invasive breast cancer, but researchers have not fully understood how it helps early, non-invasive breast lesions develop into invasive cancer. A clearer picture of this process could strengthen physicians’ ability to predict and treat the disease.
In the study, breast cancers in women without obesity displayed the typical signs of turning invasive, including rapid cell division and an increased ability to invade neighbouring tissue. In women with obesity, however, the researchers identified a different set of biological changes that appeared to help the cancer become invasive.
The cancer environment became more inflamed, with the arrival of immune cells that advanced the growth of the tumour. The tumour cells also appeared better able to survive under stress, and there were changes in cellular metabolism – how the cells use nutrients for energy.
“This could be why women with obesity are at higher risk for invasive breast cancer,” said Bethany Hannafon, Ph.D., co-lead author of the study and an assistant professor in the Department of Obstetrics and Gynecology at the OU College of Medicine. “The changes that the cancer cells are undergoing are allowing them to survive and thrive.”
A cooperative cancer “neighbourhood”
The researchers also found differences in the “neighbourhood” of cells and tissues surrounding the cancer. Epithelial cells, where the tumour originally develops, co-opt other cells around them to create an environment that is even more conducive to cancer growth.
“In women with obesity, there is cooperation between all the cell types, not just the cancer cells, which helps an early pre-cancer to become an invasive breast cancer,” said co-lead author Elizabeth Wellberg, Ph.D., assistant professor in the Department of Pathology at the OU College of Medicine. “That may be an area of future study – can a drug or intervention that targets only one cell type interrupt the whole network of progression toward invasive cancer?”
The role of the enzyme SULF2
The research team additionally discovered higher levels of an enzyme called Sulfatase 2 (SULF2) in the tumour cells of women with obesity, suggesting that it may play an important part in cancer progression. SULF2 will be a further focus of future studies.
Why better DCIS risk prediction matters
Understanding what causes early, non-invasive tumours – known as ductal carcinoma in situ, or DCIS – to become invasive is important because not all women will go on to develop invasive cancer, yet they currently receive the same treatment.
“In women diagnosed with DCIS, about half will later develop invasive ductal carcinoma (IDC) that spreads into surrounding breast tissue. But we currently have no way of determining which women are most at risk. As a result, many women with DCIS receive the same treatments used for IDC, including surgery, radiation and sometimes hormone therapy. Overtreatment is a major concern, but if we had better ways of determining risk, unnecessary treatments could potentially be reduced,” Hannafon said.
While breast cancer survival rates have improved over the past two decades, the number of women diagnosed with invasive breast cancer has not declined – underscoring the need for better ways to predict and prevent disease progression.
A growing public health concern
The rising prevalence of obesity gives the findings added weight.
“Obesity is on the rise – 50% of Americans are expected to be obese by 2030,” said the paper’s first author, Cole Hladik, Ph.D., who worked in Hannafon’s lab while earning his doctorate. “That statistic further highlights the importance of considering a patient’s metabolic health alongside the biology of the tumor itself.”
Read More