Obesity-driven estrone emerges as a key driver of deadly postmenopausal breast cancer

A new analysis of research into the most common type of breast cancer has zeroed in on an overlooked hormone that may be responsible for the increased risk of breast cancer death in post-menopausal women with obesity. It also raises the possibility that treatment of these aggressive breast cancers could be improved with addition of weight-loss drugs known as GLP-1 receptor agonists.

The most common and deadly form of this disease in women after menopauses is estrogen receptor positive (ER+) breast cancer. According to Joyce Slingerland, MD, PhD, who co-leads the Cancer Host Interaction Program at Georgetown University's Lombardi Comprehensive Cancer Center, the outlook for ER-positive breast cancer is particularly stark for postmenopausal women with obesity: They are more likely to be diagnosed with this form of the disease and they are 2-3 times more likely to die from it. 

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."

Joyce Slingerland, MD, PhD, Georgetown University's Lombardi Comprehensive Cancer Center

Slingerland's analysis provides robust evidence that, in women with obesity, the major driver is estrone, a form of estrogen that is produced in fat tissue. 

The review was published December 2 in Nature Reviews Endocrinology. 

Slingerland, the review's lead author, has led several studies that strongly connect estrone to postmenopausal ER-positive breast cancer.

"Our work has provided some of the causal links between estrone and the worse outcomes seen in postmenopausal women with ER-positive breast cancer who are obese," Slingerland said. These connections, she added, "Should prompt us to rethink how we approach treating cancer in these women." 

Prior to menopause, 17β-estradiol-which is primarily produced by the ovaries-is the most abundant estrogen in women, she explained. But after menopause, its levels fall dramatically. After menopause, the most abundant form of estrogen circulating in the blood stream and residing in breast, fat, and several other tissues, is estrone. 

And despite their very similar chemical structure, Slingerland's studies have shown that there are significant differences between what these two forms of estrogen can accomplish.

For example, 17β-estradiol turns on genes that blunt inflammation in cells, in large part by blocking the activity of a family of proteins collectively called NFκB. Slingerland's research, published in Cell Metabolism 2020, found that estrone does the exact opposite, working in tandem with NFκB to activate genes that unleash a torrent of inflammation.

"Simply put, these two estrogens are not equal to each other," Slingerland said.

In the context of obesity, levels of estrone are 2- to 4-fold higher in fat, breast, and other tissues. Slingerland's research has shown these high estrone levels propel intense inflammatory activity, setting off a cascade that causes precancerous changes and activates cancer-fueling genes. 

And in a 2022 study published in Cell Reports, Slingerland and her colleagues showed that this estrone-fueled inflammatory storm activates genes involved in a cellular process known as the epithelial-mesenchymal transition, a chief promoter of cancer metastasis. In that study, when the researchers treated obese mice with ER-positive breast cancer with estrone, their tumors not only grew faster than tumors in mice treated with 17β-estradiol, they also rapidly metastasized throughout the body.

There's also evidence that estrone and the inflammation it orchestrates dampens the immune system's ability to detect and kill cancer cells, Slingerland explains.

Based on the ample evidence linking estrone and breast cancer, clinical studies of GLP-1 drugs in women with ER-positive breast cancer who have obesity are a logical and compelling next step, she says. 

Lifestyle-focused interventions alone, such as regular exercise and dietary changes, have shown some promise in women with ER-positive breast cancer. But it's unclear whether such interventions are sustainable over the long-term and, thus, can produce meaningful clinical improvements.

"The GLP-1 drugs have revolutionized weight loss," Slingerland says. "Because of estrone's powerful inflammatory effects in fat, there's real potential that, by inducing weight loss, GLP-1 drugs can pump the brakes on estrone's cancer-fueling behavior." 

Slingerland is the article's senior author, with co-authors Maiko Sho, a Georgetown Medical student, and Rehana Qureshi, MD, PhD, from the Sylvester Comprehensive Cancer Center and Department of Pathology, University of Miami Miller School of Medicine.

The authors report having no personal financial interests related to the study. The analysis was support by a grant from the National Cancer Institute (R01CA210440) and a grant from the Breast Cancer Research Foundation.