Barrett James E, Herzog Chiara Maria, Aminzadeh-Gohari Sepideh, Redl Elisa, Ishaq Parveen Isma, Rothärmel Julia, Tevini Julia, Weber Daniela D, Catalano Luca, Stefan Victoria E, Felder Thomas K, Obrist Peter, Alkasalias Twana, Gemzell-Danielsson Kristina, Lang Roland, Kofler Barbara, Widschwendter Martin
European Translational Oncology Prevention and Screening (EUTOPS) Institute, University Innsbruck, Hall in Tirol, Austria.
Institute for Biomedical Aging Research, University Innsbruck, Innsbruck, Austria.
Commun Med (Lond). 2025 Apr 2;5(1):97. doi: 10.1038/s43856-025-00779-w.
In order to advance personalized primary cancer prevention, surrogate endpoint biomarkers in distant, easy to access tissues (i.e., field defect indicators) reflecting field cancerization in the organ at risk are essential.
Here we utilized medroxyprogesterone acetate and 7,12-dimethylbenzanthracene to induce mammary gland cancers in mice. We assessed epigenetic signatures reflective of carcinogen exposure, cell-type composition, mitotic age, and methylation at progesterone receptor binding sites in both, the tissue at risk (normal mammary gland; field cancerization) and distant non-at-risk organs (cervix, oviduct, and blood; field defect indicators), in mice that did and did not develop mammary gland cancers.
We demonstrate that the anti-progestine mifepristone reduces the cancer risk by more than 50%. Importantly, the reduction in cancer risk is accompanied by a decline in both field cancerization and field defect indicators; specifically, epigenetic signatures in the cervix are predictive of mammary cancer formation but show tissue-specific directionality.
These data encourage further exploration of epigenetic biomarkers in certain field defect-indicating tissues with a view to monitor the efficacy of cancer prevention strategies in humans.
为了推进个性化原发性癌症预防，反映有风险器官中场癌化的远处、易于获取组织（即场缺陷指标）中的替代终点生物标志物至关重要。
在这里，我们利用醋酸甲羟孕酮和7,12-二甲基苯并蒽在小鼠中诱导乳腺癌。我们评估了在有乳腺癌和没有乳腺癌的小鼠中，有风险组织（正常乳腺；场癌化）和远处无风险器官（子宫颈、输卵管和血液；场缺陷指标）中反映致癌物暴露、细胞类型组成、有丝分裂年龄和孕酮受体结合位点甲基化的表观遗传特征。
我们证明抗孕激素米非司酮可将癌症风险降低50%以上。重要的是，癌症风险的降低伴随着场癌化和场缺陷指标的下降；具体而言，子宫颈中的表观遗传特征可预测乳腺癌的形成，但显示出组织特异性方向性。
这些数据鼓励进一步探索某些场缺陷指示组织中的表观遗传生物标志物，以监测人类癌症预防策略的疗效。
