New analysis of prior research published in Nature Reviews Endocrinology identifies estrone—the dominant estrogen in postmenopausal women—as a key driver of inflammation, tumor progression, and metastasis in estrogen receptor–positive (ER+) breast cancer, particularly in women with obesity. The study highlights how estrone produced in adipose tissue creates a tumor-promoting environment distinct from the effects of premenopausal 17β-estradiol.
Joyce Slingerland, MD, PhD, co-leader of the Cancer Host Interaction Program at Georgetown University’s Lombardi Comprehensive Cancer Center, emphasized that estrone’s rise after menopause helps explain the increase in ER+ breast cancer incidence and mortality with age. “Before menopause, 17β-estradiol from the ovaries exerts anti-inflammatory effects. After menopause, its levels drop sharply, leaving estrone as the most abundant estrogen in blood, breast, and fat tissue,” she said. In obese women, estrone levels in adipose and breast tissue can be two to four times higher, fueling intense inflammatory activity.
The researchers noted that obesity causes chronic inflammation in fat tissue through pre-adipocyte expansion and activation of nuclear factor–κB (NF-κB), which increases pro-inflammatory cytokines and impairs immunosurveillance. Estrone, produced by adipocytes, further promotes NF-κB–driven inflammation, creating a microenvironment conducive to tumor growth.
This hormonal shift—from anti-inflammatory estradiol to pro-inflammatory estrone—may explain why most ER+ breast cancers occur in older women, even as overall estrogen levels decline. ER+ tumors account for more than 70% of breast cancers in women over 70, with both incidence and mortality rising post-menopause.
Slingerland’s previous research has shown that estrone works with NF-κB to activate pro-inflammatory cytokines, expand stem-like cancer cells, and stimulate invasive behavior. A 2022 Cell Reports study demonstrated that estrone accelerates tumor growth and metastasis in ER+ breast cancer mouse models by triggering epithelial-mesenchymal transition (EMT) gene programs.
The current analysis suggests this mechanism is particularly pronounced in postmenopausal women with obesity. Increased adipose tissue elevates estrone production, while chronic inflammation amplifies interactions between adipocytes and cancer cells, promoting tumor progression and metastasis.
“High mammary adipocyte estrone synthesis and chronic inflammation in obesity not only drive tumor formation but also enhance mesenchymal invasive features, promoting local invasion and metastasis,” the authors wrote. These findings align with prior work showing that the estradiol-to-estrone converting enzyme HSD17B14 accelerates metastasis in ER+ tumors.
The authors concluded that the menopausal shift—declining estradiol and rising estrone—combined with obesity-related estrone elevation, may underlie the postmenopausal rise in ER+ breast cancer incidence, risk, and mortality. They call for further studies on enzymes regulating estrone and estradiol.
Clinically, these findings could reshape treatment approaches. Because estrone is produced in fat, weight-loss interventions might reduce its pro-inflammatory effects. Slingerland highlighted the potential of GLP-1 receptor agonists and dual GLP-1/GIP agonists, already used for weight loss, as adjunct therapies in ER+ breast cancer. “By reducing fat mass, these drugs may dampen estrone’s cancer-promoting activity,” she said.
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