Overlooked hormone drives postmenopausal breast cancer in obese women

An overlooked fat-derived hormone may drive higher breast cancer death risk in postmenopausal women with obesity, an analysis suggests.

The review identifies oestrone, a form of oestrogen produced in fat tissue, as a major driver of oestrogen receptor positive (ER+) breast cancer, the most common and deadly form of the disease in postmenopausal women.

ER+ means the cancer grows in response to oestrogen. It also raises the possibility that treatment could be improved with the addition of weight-loss drugs known as GLP-1 receptor agonists.

The analysis was led by Joyce Slingerland, who co-leads the Cancer Host Interaction Program at Georgetown University’s Lombardi Comprehensive Cancer Center in the US.

She said postmenopausal women with obesity are more likely to be diagnosed with ER+ breast cancer and are two to three times more likely to die from it.

Slingerland said: “That’s particularly concerning because it’s estimated that obesity will affect nearly half of women in the United States by the end of the decade.”

Before menopause, the most abundant oestrogen in women is 17β-oestradiol, produced primarily by the ovaries.

After menopause, its levels fall dramatically and oestrone becomes the most abundant form circulating in the blood.

Despite their similar chemical structure, the research suggests these two forms of oestrogen behave very differently.

While 17β-oestradiol turns on genes that reduce inflammation, oestrone does the opposite, activating genes that trigger intense inflammatory activity.

In the context of obesity, levels of oestrone are two to four times higher in fat, breast and other tissues.

The analysis suggests these elevated levels set off a cascade that causes precancerous changes and activates cancer-fuelling genes.

Previous research by the team showed that oestrone-fuelled inflammation activates genes involved in a process that promotes cancer spread.

When researchers treated obese mice with ER+ breast cancer with oestrone, their tumours grew faster and rapidly spread throughout the body compared with mice treated with 17β-oestradiol.

Slingerland said: “Our work has provided some of the causal links between oestrone and the worse outcomes seen in postmenopausal women with ER-positive breast cancer who are obese.

“Simply put, these two oestrogens are not equal to each other.”

The author argues that clinical studies of GLP-1 drugs in women with ER+ breast cancer who have obesity are a logical next step.

Slingerland said: “The GLP-1 drugs have revolutionised weight loss.

“Because of oestrone’s powerful inflammatory effects in fat, there’s real potential that, by inducing weight loss, GLP-1 drugs can pump the brakes on oestrone’s cancer-fuelling behaviour.”