A recent analysis has highlighted a previously overlooked hormone as a key driver of deadly breast cancer in postmenopausal women with obesity. The hormone, estrone, may explain why women with obesity face a higher risk of developing and dying from the most common form of postmenopausal breast cancer. Researchers also suggest that new treatment strategies, including weight-loss drugs known as GLP-1 receptor agonists, could improve outcomes for these patients.
The most prevalent and deadly form of breast cancer after menopause is estrogen receptor positive (ER+) breast cancer.
According to Dr. Joyce Slingerland, MD, PhD, co-leader of the Cancer Host Interaction Program at Georgetown University’s Lombardi Comprehensive Cancer Center, postmenopausal women with obesity are not only more likely to develop ER+ breast cancer, but they are also two to three times more likely to die from it.
Slingerland’s review, published on December 2 in Nature Reviews Endocrinology, provides strong evidence that estrone, a form of estrogen produced in fat tissue, is a major factor in this increased risk. The review draws on years of research linking estrone to aggressive postmenopausal ER+ breast cancers.
“Through our studies, we have established causal links between estrone and the poorer outcomes seen in postmenopausal women with ER-positive breast cancer who have obesity,” Slingerland said. She added that these findings should encourage a reevaluation of treatment approaches for this group of patients.
Before menopause, 17β-estradiol—mainly produced by the ovaries—is the dominant form of estrogen. After menopause, estradiol levels drop sharply, and estrone becomes the primary estrogen circulating in the blood and accumulating in breast, fat, and other tissues. Despite their similar chemical structures, Slingerland’s research shows that the two estrogens have markedly different effects.
While 17β-estradiol helps reduce inflammation in cells, estrone intensifies it by working with proteins known as NFκB to activate inflammation-promoting genes. In women with obesity, estrone levels are two to four times higher in fat and breast tissue, triggering severe inflammation that can lead to precancerous changes and activation of genes that fuel cancer growth.
In a 2022 study published in Cell Reports, Slingerland and her team demonstrated that estrone accelerates tumor growth and metastasis in obese mice with ER+ breast cancer. They also found that estrone-driven inflammation weakens the immune system, making it harder to detect and destroy cancer cells.
Given this evidence, Slingerland believes clinical studies testing GLP-1 receptor agonists in women with obesity and ER+ breast cancer are a logical next step. While lifestyle interventions like exercise and diet changes show some benefit, they may not be sustainable long-term. GLP-1 drugs, which have transformed weight loss treatment, could reduce estrone levels and slow the cancer-promoting effects of obesity.
The study was conducted by Slingerland, with co-authors Maiko Sho, a Georgetown medical student, and Rehana Qureshi, MD, PhD, from the University of Miami. The research was funded by the National Cancer Institute and the Breast Cancer Research Foundation.
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