Joyce Slingerland, MD, PhD, notes how estrone and obesity impact breast cancer risk postmenopause

In a recent interview with Contemporary OB/GYN, Joyce Slingerland, MD, PhD, professor at Lombardi Comprehensive Cancer Center, described emerging evidence linking estrone to increased breast cancer risk and progression in postmenopausal women with obesity.

Epidemiologic data show that obesity raises postmenopausal breast cancer risk by approximately 1.4-fold and doubles to triples the risk of breast cancer–related death across subtypes. This heightened risk is most apparent after menopause, prompting investigators to explore how hormonal drivers differ before and after ovarian estrogen production declines.

Before menopause, estradiol is the dominant estrogen and is produced by the ovaries. Estradiol is highly potent and, in many experimental systems, shows anti-inflammatory properties. After menopause, however, estrone becomes the dominant estrogen. Estrone is generated through peripheral conversion of adrenal androgens, such as androstenedione, in adipose tissue. In women with obesity, increased fat mass leads to nearly 2-fold greater estrone levels, creating a distinctly pro-inflammatory hormonal environment.

Slingerland’s laboratory studies directly compared estrone and estradiol and found that, despite its weaker receptor binding, estrone stimulated more rapid breast cancer growth in mouse models. Estrone was also shown to activate the NF-κB pathway, one of the body’s most powerful pro-inflammatory signaling cascades.

Unlike estradiol, which can attenuate inflammation in some tissues, estrone appears to cooperate with NF-κB to drive inflammation, expand breast cancer stem cell populations, and promote metastasis in both cell culture and animal models. These findings suggest that elevated estrone levels in obesity are particularly harmful, making postmenopausal obesity a significant risk factor for estrogen receptor–positive breast cancer and likely influencing ER-negative disease through inflammatory mechanisms.

Slingerland also discussed the potential role of GLP-1 receptor agonists in opposing these risks. She suggested these medications could be valuable tools to promote weight loss in breast cancer survivors after completion of surgery, radiation, and chemotherapy, including those on endocrine therapy. Because adipose tissue is hormonally active and rich in estrone production, reducing fat mass may lower inflammatory signaling that drives tumor progression across breast cancer subtypes.

Clinically, she emphasized that weight loss and regular exercise should be strongly promoted for breast cancer patients and their families. Future research is focused on testing GLP-1 receptor agonists, alone or combined with exercise, to determine whether they can reduce inflammation, restore anti-tumor immune function, and improve survivorship outcomes. The key message for patients is clear: sustained weight management and physical activity may play an important role in reducing recurrence risk and improving long-term outcomes.

No relevant disclosures.

Reference

An overlooked hormone eyed as deadly driver of postmenopausal breast cancer in women with obesity. Georgetown University Medical Center. December 2, 2025. Accessed December 8, 2025. https://www.eurekalert.org/news-releases/1107155