Obesity May Remove a Natural Defense Against Breast Cancer

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.

“We uncovered the role of a molecule that normally appears in lean tissue that restrains breast cancer growth but is less present with obesity,” says Keren Hilgendorf, PhD, Huntsman Cancer Institute investigator, assistant professor of biochemistry at the U, and senior author of the study. “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.”

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.

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.

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.

“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 their preclinical mouse models, Hilgendorf and Curtin found that increasing the amount of 9S-HODE in obese adipocytes suppressed breast cancer tumor growth. They believe this new understanding could lead to better therapies.

“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.”

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.

“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.