A team from the Institut Curie, Inserm, and CNRS[1] has uncovered a new molecular mechanism, previously unknown, linking estrogens (female sex hormones) to the worsening of certain cancers not traditionally considered hormone-dependent, such as melanoma, gastric cancer, and thyroid cancer.
This research, published in
Nature on June 11, 2025, paves the way for new therapeutic strategies, particularly for women of childbearing age.
Cross-section of a melanoma with MTA CD163+ (tumor-associated macrophages) stained in green, blood vessels stained in red, and cell nuclei stained in gray. © 2019 Etzerodt et al. An underestimated hormonal role in cancers
While it is accepted that hormone-dependent cancers account for about 20% of cancer cases worldwide[2], this new study challenges this understanding. Through a large epidemiological analysis, researchers observed that several cancers, particularly melanoma, are more common in women between puberty and menopause than in men of the same age—a period marked by high exposure to estrogens.
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Empirically, dermatologists had already noted a higher incidence of melanomas in young women, especially after pregnancy. We sought to scientifically understand this phenomenon," explains Dr. Lionel Larue, research director at Inserm, team leader at the Institut Curie, and co-senior author of the study.
A novel pro-metastatic molecular loop
The analyses revealed a previously unknown signaling pathway strictly dependent on the female hormonal environment. This regulatory loop involves key molecular players, including ESR1 (the estrogen receptor), which induces the GRPR receptor (for
Gastrin-releasing peptide receptor), triggering the activation of the pro-metastatic YAP1 pathway[3]. This, in turn, represses E-cadherin (ECAD), a cell-cell adhesion molecule whose reduction facilitates tumor progression. The loop is closed by the induction of ESR1 transcription following the decrease in ECAD levels.
Thus, this mechanism promotes tumor growth, migration, and invasion of cancer cells, as well as their resistance to anoikis[4]—a process of cell death normally involved in preventing metastatic spread. This process is particularly active in women, as it depends on the activation of the ESR1 receptor by estrogens.
A promising new therapeutic target
Notably, GRPR belongs to the G protein-coupled receptor (GPCR) family, which represents 35% of the targets of currently approved drugs but remains underutilized in oncology. By administering specific GRPR antagonists in preclinical models, researchers observed a significant reduction in metastasis formation.
Beyond its role in tumor progression, GRPR also plays a part in pain perception. Its modulation could therefore both slow metastases and improve patients' quality of life. The development of combined anti-estrogenic therapies could be a relevant approach for treating melanomas and other cancers exhibiting this metastatic loop.
Age and sex at the heart of tomorrow's personalized medicine
This major discovery highlights a new facet of sex-based disparities in cancer and underscores the importance of better integrating hormonal and biological factors into prevention, diagnosis, and treatment. It also offers new perspectives for repurposing existing drugs for oncology applications.
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Better understanding the impact of sex and age on the development of certain cancers is essential for advancing precision medicine. This work lays the foundation for innovative therapeutic approaches, particularly for women, and opens concrete clinical prospects," concludes Dr. Lionel Larue, research director at Inserm.
Notes:
[1] This research was conducted by Dr. Lionel Larue, research director at Inserm, head of the Normal and Pathological Development of Melanocytes team in the Signaling, Radiobiology, and Cancer unit (Institut Curie, Inserm, CNRS, Université Paris Saclay), and Dr. Véronique Delmas, research director at CNRS in the same team.
[2] Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA CANCER J CLIN 71, (2021).
[3] The YAP-1 pathway is an essential cellular mechanism regulating cell growth and survival. Its dysfunction is implicated in several diseases, including cancer, making it a promising target for new therapies.
[4] Anoikis is a programmed cell death process that occurs when cells lose their anchorage to their environment. This mechanism is crucial for maintaining tissue homeostasis and plays an important role in embryonic development, wound healing, and preventing tumor formation.