Androgen Receptors Amplify Breast Tumor Progression in Obese Rats

New findings show tumor growth in obese rats is driven by especially sensitive androgen receptors.

The androgen receptor has context-dependent roles in the growth and progression of breast cancer. Although high tumor androgen receptor levels predict favorable patient outcomes, several studies have indicated these receptors promote tumor growth—–particularly in ER-positive breast cancers after endocrine therapy.

In a study published in Hormones & Cancer, investigators sought to examine the potential role of androgen receptors in obesity-associated mammary tumors, post endocrine therapy.

“Our original goal was to make a model of obesity and breast cancer that would reflect the condition in women,” said first author Elizabeth Wellberg, PhD. “At first, we were disappointed to discover that rats don’t make much estrogen in fat tissue like humans do. But we then realized that this aspect of the model gave us an excellent opportunity to study cancer progression after anti-estrogen treatment.

“Because fat cells in these rats don’t make estrogen, they are like human breast cancer patients treated to remove estrogen. This allowed us to ask what is responsible for obesity-associated tumor progression in conditions of low estrogen availability.”

In the animal models of obesity and breast cancer, investigators found the tumor cells had especially sensitive androgen receptors in obese animals, but not lean animals. This allowed the cells to magnify growth signals from the hormone testosterone.

The obese rats were treated with the anti-androgen drug enzalutamide. The findings showed the drug shrank existing tumors and new tumors did not develop. The question still remains, however, as to what is creating these overactive androgen receptors.

“When you talk about what’s different between lean and obese individuals there are a lot of things—–resistance to insulin, high sugar, and an elevated inflammatory response, what we call chronic low-grade inflammation, to name a few,” said author Steven Anderson, PhD. “In a lot of ways, you can walk through these differences looking for what may be causing this androgen receptor sensitivity.”

In prior studies, the investigators showed that a component of inflammation, particularly levels of interleukin 6 (IL-6), is higher in obese rats compared with lean rats. In the current study, the investigators showed that administering IL-6 to breast cancer cells magnifies androgen receptor activity.

The findings add to the growing body of evidence that obesity should be considered as a variable in the clinic.

“Down the line, we can imagine a day in which the BMI or metabolic state of breast cancer patients would be considered when choosing a treatment,” Dr Wellberg said. “These patients may benefit significantly from a more personalized therapeutic strategy, based on what obesity is doing to the tumor environment.”

An estimated 40% of women in the United States are obese, and approximately 75% are estrogen-receptor positive.