A team from the Institut Curie, Inserm and CNRS [1] has uncovered a hitherto unknown molecular mechanism linking estrogens (female sex hormones) to the aggravation of certain cancers not traditionally considered hormone-dependent, such as melanoma, gastric cancer and thyroid cancer.minine sex hormones) to the aggravation of certain cancers not traditionally considered hormone-dependent, such as melanoma, gastric cancer and thyroid cancer. This work, published in Nature on June 11, 2025, opens the way to new therapeutic strategies, particularly for women of childbearing age.
A hormonal role in cancer long underestimated
While it is generally accepted that hormone-dependent cancers account for around 20% of all cancer cases worldwide [2] , this new study questions this assessment. based on an extensive epidemiological analysis, the researchers found that several cancers, notably melanoma, are more frequent in women between puberty and adulthood.women between puberty and menopause than in men at the same age, a period marked by high exposure to estrogen.
" Empirically, dermatologists had already observed a higher incidence of melanoma in young women, particularly after pregnancy. We set out to understand this phenomenon scientifically ", explains Dr Lionel Larue, Director of Research at Inserm, team leader at the Institut Curie and co-latest author of the study.
A novel pro-metastatic molecular loop
The analyses carried out identified a hitherto unknown signalling pathway, strictly dependent on the female hormonal environment. This regulatory loop involves a number of key molecular players, including ESR1 (the estrogen receptor), which induces the GRPR receptor ( Gastrin-releasing peptide receptor), leading to activation of the pro-metastatic pathway.leading to activation of the pro-metastatic YAP1 pathway [3], which represses E-cadherin (ECAD), a cell-cell adhesion molecule whose depletion facilitates tumor progression. The loop is closed by induction of ESR1 transcription after ECAD levels have been reduced.
Thus, this mechanism promotes tumor growth, migration and invasion of tumor cells, as well as their resistance to anoikis [4] - a cell death process normally involved in preventing metastatic spread. And this process is particularly active in women, since it depends on estrogen activation of the ESR1 receptor.
A promising new therapeutic target
Remarkably, GRPR belongs to the family of G protein-coupled receptors (GPCRs), which account for 35% of currently approved drug targets, but remain under-exploited in oncology. By administering specific GRPR antagonists in preclinical models, researchers observed a significant reduction in metastasis formation. In addition to its involvement in tumor progression, GRPR also plays a role in pain perception. Its modulation could therefore both slow down metastasis and improve patients’ quality of life. The introduction of combined anti-estrogen therapies could be a relevant approach in the treatment of melanoma, and other cancers, presenting this metastatic loop.
Age and gender at the heart of tomorrow’s personalized medicine
This major discovery highlights a new facet of gender inequalities in cancer, and underscores the importance of better integrating hormonal and biological factors into prevention, diagnosis and treatment. It also offers new prospects for reorienting existing drugs towards use in oncology.
" A better understanding of the impact of gender and age on the development of certain cancers is essential for advancing precision medicine. This work lays the foundations for innovative therapeutic approaches, prevalent in women, and opens up concrete clinical prospects ", concludes Dr Lionel Larue, Director of Research at Inserm.
[1] This work was carried out by Dr Lionel Larue, Inserm Research Director, head of the Normal and Pathological Development of Melanocytes team in thesignalisation, radiobiologie et cancer unit (Institut Curie, Inserm, CNRS, Université Paris Saclay) and Dr Véronique Delmas, CNRS research director 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 that regulates 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 process of programmed cell death that occurs when cells lose their anchorage to their environment. This mechanism is crucial for the maintenance of tissue homeostasis and plays an important role in embryonic development, wound healing and the prevention of tumor formation.
Targeting GRPR for sex hormone-dependent cancer after loss of E-cadherin.
Jérémy H. Raymond, Zackie Aktary, Marie Pouteaux, Valérie Petit, Flavie Luciani, Maria Wehbe, Patrick Gizzi, Claire Bourban, Didier Decaudin, Fariba Nemati, Igor Martianov, Irwin Davidson, Catherine-Laure Tomasetto, Richard M. White, Florence-Mahuteau Betzer, Béatrice Vergier, Lionel Larue*, and Véronique Delmas*. Nature, June 11, 2025.
* co-last author. Lionel Larue is the corresponding author
https://doi.org/10.1038/s41586-025-09111-x
